Hydroxyprogesterone caproate

Identification

Summary

Hydroxyprogesterone caproate is a synthetic progestin used for the prevention of spontaneous preterm births in singleton pregnancies in women who have previously had a spontaneous preterm birth.

Brand Names
Makena
Generic Name
Hydroxyprogesterone caproate
DrugBank Accession Number
DB06789
Background

Hydroxyprogesterone caproate is a synthetic steroid hormone that is similar to medroxyprogesterone acetate and megestrol acetate. It is an ester derivative of 17α-hydroxyprogesterone formed from caproic acid (hexanoic acid). Hydroxyprogesterone caproate was previously marketed under the trade name Delalutin by Squibb, which was approved by the U.S. Food and Drug Administration (FDA) in 1956 and withdrawn from marketing in 1999. The U.S. FDA approved Makena from KV Pharmaceutical (previously named as Gestiva) on February 4, 2011 for prevention of preterm delivery in women with a history of preterm delivery, sparking a pricing controversy.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 428.6041
Monoisotopic: 428.292659768
Chemical Formula
C27H40O4
Synonyms
  • 17-alpha-hydroxy-progesterone caproate
  • 17alpha-Caproyloxypregn-4-ene-3,20-dione
  • 17alpha-Hydroxyprogesterone hexanoate
  • Caproate d'hydroxyprogesterone
  • Caproato de hidroxiprogesterona
  • Hydroxyprogesterone caproate
  • Hydroxyprogesterone hexanoate
External IDs
  • NSC-17592

Pharmacology

Indication

Hydroxyprogesterone caproate is indicated for the prevention of spontaneous preterm births in singleton pregnancies in women who have previously had a spontaneous preterm birth. (1)

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

No specific pharmacodynamic studies have been performed to assess hydroxyprogesterone caproate injections. (4) However, the mechanism of action is likely related to increased interaction between progesterone and progesterone receptors. (5)

Mechanism of action

The mechanism by which progesterone prevents preterm birth is not well understood, but many pathways are likely involved. (1) Progesterone plays a vital role in regulation of the female reproductive system and is important for successful implantation of the embryo and maintenance of pregnancy. It acts by binding to progesterone receptors in the uterus, ovaries, breasts and in the central nervous system. These receptors exist in 2 isoforms, PR-A and PR-B. Progesterone binding to these receptors ultimately leads to regulation of gene transcription. (2) This results in an anti-inflammatory effect which blunts the proinflammatory state that occurs with initiation of labor, and maintains uterine queiscence by stabilizing progesterone acting on the myometrium. (2)

TargetActionsOrganism
UProgesterone receptor
agonist
Humans
Absorption

Absorption of 17-hydroxyprogesteron caproate is slow, occurring over a long period of time. (3)

Volume of distribution

Hydroxyprogesterone caproate has a high volume of distribution. (3)

Protein binding

Hydroxyprogesterone caproate is extensively protein bound in the plasma. (3)

Metabolism

The main enzymes involved in metabolism of hydroxyprogesterone caproate are cytochrome P450 (CYP) 3A4 and to a lesser extent CYP3A5. (3)

Route of elimination

Following intramuscular injection, approximately 50% of hydroxyprogesterone caproate metabolites are eliminated in the feces, while approximately 30% of metabolites are eliminated in the urine. (3)

Half-life

Half-life = 16 days (±6 days). (3)

Clearance

Clearance is highly variable from patient to patient. (3)

Adverse Effects
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Toxicity

Injection site pain is the most common adverse effect associated with hydroxyprogesterone caproate. Other commonly reported adverse effects include: injection site swelling, urticaria, pruritus, injection site pruritus, nausea, injection site nodule, and diarrhea. (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.
DrugInteraction
AbametapirThe serum concentration of Hydroxyprogesterone caproate can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Hydroxyprogesterone caproate can be increased when combined with Abatacept.
AbciximabHydroxyprogesterone caproate may decrease the anticoagulant activities of Abciximab.
AcalabrutinibThe metabolism of Hydroxyprogesterone caproate can be decreased when combined with Acalabrutinib.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Hydroxyprogesterone caproate.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Hydroxyprogesterone caproate.
AcetaminophenThe metabolism of Hydroxyprogesterone caproate can be increased when combined with Acetaminophen.
AcetazolamideThe metabolism of Hydroxyprogesterone caproate can be increased when combined with Acetazolamide.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be decreased when used in combination with Hydroxyprogesterone caproate.
AcitretinThe therapeutic efficacy of Hydroxyprogesterone caproate can be decreased when used in combination with Acitretin.
Interactions
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Food Interactions
No interactions found.

Products

Products
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International/Other Brands
Delalutin (Bristol-Myers Squibb) / Gestiva (Cytyc) / Hormofort (Kobanyai) / ldrogestene (Farmila)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MakenaInjection250 mg/1mLIntramuscularAMAG Pharmaceuticals, Inc.2011-02-03Not applicableUS flag
MakenaInjection250 mg/1mLIntramuscularAMAG Pharmaceuticals, Inc.2011-02-03Not applicableUS flag
MakenaInjection250 mg/1mLSubcutaneousAMAG Pharmaceuticals, Inc.2018-02-14Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Hydroxyprogesterone CaproateInjection250 mg/1mLIntramuscularMylan Institutional LLC2019-08-23Not applicableUS flag
Hydroxyprogesterone CaproateInjection250 mg/1mLIntramuscularAMERICAN REGENT, INC.2018-06-28Not applicableUS flag
Hydroxyprogesterone CaproateInjection250 mg/1mLIntramuscularPrasco Laboratories2018-07-02Not applicableUS flag
Hydroxyprogesterone caproateInjection250 mg/1mLIntramuscularGP PHARM SA2019-03-01Not applicableUS flag
Hydroxyprogesterone CaproateInjection250 mg/1mLIntramuscularANI Pharmaceuticals, Inc.2016-06-032018-07-31US flag
Hydroxyprogesterone CaproateInjection250 mg/1mLIntramuscularAuroMedics Pharma LLC2019-04-16Not applicableUS flag
Hydroxyprogesterone CaproateInjection250 mg/1mLIntramuscularSun Pharmaceutical Industries, Inc.2019-07-01Not applicableUS flag
Hydroxyprogesterone CaproateInjection250 mg/1mLIntramuscularMylan Institutional LLC2017-09-22Not applicableUS flag
Hydroxyprogesterone CaproateInjection250 mg/1mLIntramuscularAmneal Pharmaceuticals of NY LLC2019-03-11Not applicableUS flag
Hydroxyprogesterone CaproateInjection1250 mg/5mLIntramuscularAuroMedics Pharma LLC2019-05-09Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as gluco/mineralocorticoids, progestogins and derivatives. These are steroids with a structure based on a hydroxylated prostane moiety.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Pregnane steroids
Direct Parent
Gluco/mineralocorticoids, progestogins and derivatives
Alternative Parents
Steroid esters / 20-oxosteroids / 3-oxo delta-4-steroids / Delta-4-steroids / Cyclohexenones / Alpha-acyloxy ketones / Carboxylic acid esters / Monocarboxylic acids and derivatives / Organic oxides / Hydrocarbon derivatives
Substituents
20-oxosteroid / 3-oxo-delta-4-steroid / 3-oxosteroid / Aliphatic homopolycyclic compound / Alpha-acyloxy ketone / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Cyclic ketone / Cyclohexenone
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
corticosteroid hormone (CHEBI:5812)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
276F2O42F5
CAS number
630-56-8
InChI Key
DOMWKUIIPQCAJU-LJHIYBGHSA-N
InChI
InChI=1S/C27H40O4/c1-5-6-7-8-24(30)31-27(18(2)28)16-13-23-21-10-9-19-17-20(29)11-14-25(19,3)22(21)12-15-26(23,27)4/h17,21-23H,5-16H2,1-4H3/t21-,22+,23+,25+,26+,27+/m1/s1
IUPAC Name
(1R,3aS,3bR,9aR,9bS,11aS)-1-acetyl-9a,11a-dimethyl-7-oxo-1H,2H,3H,3aH,3bH,4H,5H,7H,8H,9H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthren-1-yl hexanoate
SMILES
[H][C@@]12CC[C@](OC(=O)CCCCC)(C(C)=O)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])CCC2=CC(=O)CC[C@]12C

References

Synthesis Reference

U.S. Patent 2,753,360.

General References
  1. Goodnight W: Clinical Application of Progesterone for the Prevention of Preterm Birth, 2016. Am J Perinatol. 2016 Feb;33(3):253-7. doi: 10.1055/s-0035-1570378. Epub 2016 Jan 20. [Article]
  2. Ruan X, Mueck AO: Systemic progesterone therapy--oral, vaginal, injections and even transdermal? Maturitas. 2014 Nov;79(3):248-55. doi: 10.1016/j.maturitas.2014.07.009. Epub 2014 Jul 22. [Article]
  3. Feghali M, Venkataramanan R, Caritis S: Prevention of preterm delivery with 17-hydroxyprogesterone caproate: pharmacologic considerations. Semin Perinatol. 2014 Dec;38(8):516-22. doi: 10.1053/j.semperi.2014.08.013. Epub 2014 Sep 23. [Article]
  4. O'Brien JM, Lewis DF: Prevention of preterm birth with vaginal progesterone or 17-alpha-hydroxyprogesterone caproate: a critical examination of efficacy and safety. Am J Obstet Gynecol. 2016 Jan;214(1):45-56. doi: 10.1016/j.ajog.2015.10.934. Epub 2015 Nov 10. [Article]
KEGG Drug
D00949
KEGG Compound
C08148
PubChem Compound
169870
PubChem Substance
310264886
ChemSpider
148552
BindingDB
70293
RxNav
12488
ChEBI
5812
ChEMBL
CHEMBL1200848
ZINC
ZINC000004083606
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Hydroxyprogesterone_caproate
FDA label
Download (383 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingPreventionPremature Births1
4RecruitingTreatmentAbortions spontaneous / Ovarian Hyperstimulation Syndrome / Pregnancy Early1
3Active Not RecruitingTreatmentLocally Advanced Breast Cancer and Large Operable Breast Cancer1
3CompletedPreventionHuman Immunodeficiency Virus Type 1 (HIV-1) Infection / Pre-Term Birth1
3CompletedPreventionNeonatal Complications / Preterm Delivery1
3CompletedPreventionPremature Births1
3TerminatedTreatmentAssessing Injection Pain of Makena® (Hydroxyprogesterone Caproate Injection, 250 mg/mL) in Healthy Post-menopausal Women1
3Unknown StatusPreventionObstetric Labour, Premature / Premature Births1
3Unknown StatusPreventionPregnant State1
2CompletedNot AvailablePreterm Delivery1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntramuscular1250 mg/5mL
InjectionIntramuscular250 mg/1mL
LiquidIntramuscular250 mg/1mL
PowderNot applicable1 kg/1kg
Injection, solution
Injection, solutionIntramuscular
Injection, solutionParenteral
InjectionSubcutaneous250 mg/1mL
SolutionParenteral
SolutionParenteral250 mg
Injection, suspension, extended releaseIntramuscular; Parenteral
Injection, emulsionIntramuscular
InjectionIntramuscular
SolutionIntramuscular500 mg
SolutionIntramuscular250 mg
Solution250 mg/1ml
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
USRE44846No2014-04-152019-08-10US flag
US8021335No2011-09-202026-10-04US flag
US8562564No2013-10-222026-01-24US flag
US9533102No2017-01-032026-01-24US flag
US9629959No2017-04-252026-01-24US flag
US9844558No2017-12-192036-05-02US flag
US9180259No2015-11-102026-01-24US flag
US9789257No2017-10-172034-02-11US flag
US10471075No2019-11-122036-05-02US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)119-121U.S. Patent 2,753,360.
Predicted Properties
PropertyValueSource
Water Solubility0.000866 mg/mLALOGPS
logP4.81ALOGPS
logP5.88ChemAxon
logS-5.7ALOGPS
pKa (Strongest Acidic)17.75ChemAxon
pKa (Strongest Basic)-4.8ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area60.44 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity121.69 m3·mol-1ChemAxon
Polarizability50.28 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0aba-3940000000-835c32531e48d578d8ee

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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. O'Brien JM, Lewis DF: Prevention of preterm birth with vaginal progesterone or 17-alpha-hydroxyprogesterone caproate: a critical examination of efficacy and safety. Am J Obstet Gynecol. 2016 Jan;214(1):45-56. doi: 10.1016/j.ajog.2015.10.934. Epub 2015 Nov 10. [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. Feghali M, Venkataramanan R, Caritis S: Prevention of preterm delivery with 17-hydroxyprogesterone caproate: pharmacologic considerations. Semin Perinatol. 2014 Dec;38(8):516-22. doi: 10.1053/j.semperi.2014.08.013. Epub 2014 Sep 23. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
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 oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Feghali M, Venkataramanan R, Caritis S: Prevention of preterm delivery with 17-hydroxyprogesterone caproate: pharmacologic considerations. Semin Perinatol. 2014 Dec;38(8):516-22. doi: 10.1053/j.semperi.2014.08.013. Epub 2014 Sep 23. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
Curator comments
The data supporting CYP2C19 enzyme induction currently available is limited to in vitro studies.
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Zhao Y, Alshabi AM, Caritis S, Venkataramanan R: Impact of 17-alpha-hydroxyprogesterone caproate on cytochrome P450s in primary cultures of human hepatocytes. Am J Obstet Gynecol. 2014 Oct;211(4):412.e1-6. doi: 10.1016/j.ajog.2014.03.048. Epub 2014 Mar 26. [Article]

Drug created on September 14, 2010 16:21 / Updated on February 21, 2021 18:52