Clomifene

Identification

Summary

Clomifene is a medication used to induce ovulation.

Brand Names
Clomid
Generic Name
Clomifene
DrugBank Accession Number
DB00882
Background

A triphenyl ethylene stilbene derivative which is an estrogen agonist or antagonist depending on the target tissue.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 405.96
Monoisotopic: 405.18594223
Chemical Formula
C26H28ClNO
Synonyms
  • 2-(4-(2-chloro-1,2-diphenylethenyl)phenoxy)-N,N-diethylethanamine
  • 2-(p-(2-chloro-1,2-diphenylvinyl)phenoxy)triethylamine
  • 2-(p-(β-chloro-α-phenylstyryl)phenoxy)triethylamine
  • Clomifene
  • Clomifeno
  • Clomifenum
  • Clomiphene

Pharmacology

Indication

Used mainly in female infertility due to anovulation (e.g. due to polycystic ovary syndrome) to induce ovulation.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofOvulatory dysfunction••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Clomifene (previously clomiphene) is an orally administered, non steroidal, ovulatory stimulant that acts as a selective estrogen receptor modulator (SERM). Clomifene can lead to multiple ovulation, and hence increase the risk of conceiving twins. In comparison to purified FSH, the rate of ovarian hyperstimulation syndrome is low. There may be an increased risk of ovarian cancer and weight gain. Clomifene is capable of interacting with estrogen-receptor-containing tissues, including the hypothalamus, pituitary, ovary, endometrium, vagina, and cervix. It may compete with estrogen for estrogen-receptor-binding sites and may delay replenishment of intracellular estrogen receptors. Clomifene initiates a series of endocrine events culminating in a preovulatory gonadotropin surge and subsequent follicular rupture. The first endocrine event, in response to a course of clomifene therapy, is an increase in the release of pituitary gonadotropins. This initiates steroidogenesis and folliculogenesis resulting in growth of the ovarian follicle and an increase in the circulating level of estradiol. Following ovulation, plasma progesterone and estradiol rise and fall as they would in a normal ovulatory cycle.

Mechanism of action

Clomifene has both estrogenic and anti-estrogenic properties, but its precise mechanism of action has not been determined. Clomifene appears to stumulate the release of gonadotropins, follicle-stimulating hormone (FSH), and leuteinizing hormone (LH), which leads to the development and maturation of ovarian follicle, ovulation, and subsequent development and function of the coprus luteum, thus resulting in pregnancy. Gonadotropin release may result from direct stimulation of the hypothalamic-pituitary axis or from a decreased inhibitory influence of estrogens on the hypothalamic-pituitary axis by competing with the endogenous estrogens of the uterus, pituitary, or hypothalamus. Clomifene has no apparent progestational, androgenic, or antrandrogenic effects and does not appear to interfere with pituitary-adrenal or pituitary-thyroid function.

TargetActionsOrganism
AEstrogen receptor alpha
antagonist
agonist
Humans
USex hormone-binding globulinNot AvailableHumans
Absorption

Based on early studies with 14 C-labeled clomifene, the drug was shown to be readily absorbed orally in humans.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Hepatic

Route of elimination

Based on early studies with 14C-labeled clomiphene citrate, the drug was shown to be readily absorbed orally in humans and excreted principally in the feces. Mean urinary excretion was approximately 8% with fecal excretion of about 42%.

Half-life

5-7 days

Clearance

Not Available

Adverse Effects
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Toxicity

The acute oral LD50 of clomifene is 1700 mg/kg in mice and 5750 mg/kg in rats. The toxic dose in humans is not known. Toxic effects accompanying acute overdosage of clomifene have not been reported. Signs and symptoms of overdosage as a result of the use of more than the recommended dose during clomifene therapy include nausea, vomiting, vasomotor flushes, visual blurring, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain.

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
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Clomifene.
AbrocitinibThe serum concentration of Clomifene can be increased when it is combined with Abrocitinib.
AdagrasibThe serum concentration of Clomifene can be increased when it is combined with Adagrasib.
AfatinibThe serum concentration of Clomifene can be increased when it is combined with Afatinib.
AmbrisentanThe serum concentration of Ambrisentan can be increased when it is combined with Clomifene.
Food Interactions
  • Take with or without food. The absorption is unaffected by food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Clomifene citrate1B8447E7YI50-41-9PYTMYKVIJXPNBD-UHFFFAOYSA-N
Product Images
International/Other Brands
Androxal / Clomifert / Clostilbegyt (Egis) / Omifin (Sanofi)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ClomidTablet50 mg/1OralSanofi Aventis1967-02-012014-08-21US flag
ClomidTablet50 mgOralSanofi Aventis1995-12-312020-07-15Canada flag
Clomid 50mgTablet50 mg / tabOralMerrell Pharms Inc., Division Of Merrell Dow (Can)1967-12-311996-09-09Canada flag
SeropheneTablet50 mg/1OralPhysicians Total Care, Inc.1982-03-222013-06-30US flag
SeropheneTablet50 mg/1OralEmd Serono1982-03-222014-11-30US flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ClomidTablet50 mg/1OralCosette Pharmaceuticals, Inc.2022-09-09Not applicableUS flag
ClomidTablet50 mg/1OralA-S Medication Solutions2022-09-09Not applicableUS flag
Clomiphene CitrateTablet50 mg/1OralNucare Pharmaceuticals,inc.1999-08-30Not applicableUS flag
Clomiphene CitrateTablet50 mg/1Oralbryant ranch prepack1999-08-302025-02-28US flag
Clomiphene CitrateTablet50 mg/1OralA-S Medication Solutions1990-10-01Not applicableUS flag

Categories

ATC Codes
G03GB02 — Clomifene
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Stilbenes
Sub Class
Not Available
Direct Parent
Stilbenes
Alternative Parents
Diphenylmethanes / Phenoxy compounds / Phenol ethers / Alkyl aryl ethers / Trialkylamines / Vinyl chlorides / Chloroalkenes / Organopnictogen compounds / Organochlorides / Hydrocarbon derivatives
Substituents
Alkyl aryl ether / Amine / Aromatic homomonocyclic compound / Benzenoid / Chloroalkene / Diphenylmethane / Ether / Haloalkene / Hydrocarbon derivative / Monocyclic benzene moiety
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
tertiary amine (CHEBI:3752)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
1HRS458QU2
CAS number
911-45-5
InChI Key
GKIRPKYJQBWNGO-UHFFFAOYSA-N
InChI
InChI=1S/C26H28ClNO/c1-3-28(4-2)19-20-29-24-17-15-22(16-18-24)25(21-11-7-5-8-12-21)26(27)23-13-9-6-10-14-23/h5-18H,3-4,19-20H2,1-2H3
IUPAC Name
{2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]ethyl}diethylamine
SMILES
CCN(CC)CCOC1=CC=C(C=C1)C(=C(Cl)C1=CC=CC=C1)C1=CC=CC=C1

References

Synthesis Reference

Allen, R.E., Palopoli, F.P., Schumann, E.L. and Van Carnpen, M.G. Jr.; US. Patent 2,914,563; November 24, 1959; assigned to The Wrn. S. Merrell Company.

General References
  1. Purvin VA: Visual disturbance secondary to clomiphene citrate. Arch Ophthalmol. 1995 Apr;113(4):482-4. [Article]
  2. Hayon T, Atlas L, Levy E, Dvilansky A, Shpilberg O, Nathan I: Multifactorial activities of nonsteroidal antiestrogens against leukemia. Cancer Detect Prev. 2003;27(5):389-96. [Article]
  3. Fritz MA, Holmes RT, Keenan EJ: Effect of clomiphene citrate treatment on endometrial estrogen and progesterone receptor induction in women. Am J Obstet Gynecol. 1991 Jul;165(1):177-85. [Article]
  4. Hughes E, Brown J, Collins JJ, Vanderkerchove P: Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD000057. doi: 10.1002/14651858.CD000057.pub2. [Article]
  5. Brown J, Farquhar C, Beck J, Boothroyd C, Hughes E: Clomiphene and anti-oestrogens for ovulation induction in PCOS. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD002249. doi: 10.1002/14651858.CD002249.pub4. [Article]
  6. Authors unspecified: Use of clomiphene citrate in women. Fertil Steril. 2006 Nov;86(5 Suppl 1):S187-93. [Article]
  7. Homburg R: Oral agents for ovulation induction--clomiphene citrate versus aromatase inhibitors. Hum Fertil (Camb). 2008 Mar;11(1):17-22. doi: 10.1080/14647270701689670. [Article]
  8. Homburg R: Clomiphene citrate--end of an era? A mini-review. Hum Reprod. 2005 Aug;20(8):2043-51. Epub 2005 May 5. [Article]
Human Metabolome Database
HMDB0015020
KEGG Drug
D07726
KEGG Compound
C06917
PubChem Compound
2800
PubChem Substance
46504463
ChemSpider
2698
RxNav
2596
ChEBI
3752
ChEMBL
CHEMBL2355051
Therapeutic Targets Database
DAP001013
PharmGKB
PA449046
RxList
RxList Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Clomifene

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentInfertility / PCO - Polycystic Ovaries1
4Active Not RecruitingTreatmentInfertility / Polycystic Ovarian Syndrome (PCOS)1
4CompletedNot AvailableFemale Infertility1
4CompletedDiagnosticOvulatory Dysfunction / Unexplained Infertility1
4CompletedSupportive CarePolycystic Ovarian Syndrome (PCOS)1

Pharmacoeconomics

Manufacturers
  • Sanofi aventis us llc
  • Par pharmaceutical inc
  • Milex products inc
  • Emd serono inc
Packagers
  • Dispensing Solutions
  • Diversified Healthcare Services Inc.
  • EMD Canada Inc.
  • Medisca Inc.
  • Merrell Pharmaceuticals Inc.
  • Nucare Pharmaceuticals Inc.
  • Par Pharmaceuticals
  • Patheon Inc.
  • Pharmaceutical Utilization Management Program VA Inc.
  • Physicians Total Care Inc.
  • Preferred Pharmaceuticals Inc.
  • Qualitest
  • Rebel Distributors Corp.
  • Redpharm Drug
  • Sanofi-Aventis Inc.
  • Teva Pharmaceutical Industries Ltd.
  • Watson Pharmaceuticals
Dosage Forms
FormRouteStrength
TabletOral50 mg / tab
TabletOral
TabletOral50 mg/1
TabletOral50.000 mg
TabletOral50 mg
Capsule
Prices
Unit descriptionCostUnit
ClomiPHENE Citrate 30 50 mg tablet Box215.9USD box
Clomiphene citrate powder47.74USD g
Clomid 50 mg tablet17.1USD tablet
Serophene 50 mg tablet11.08USD tablet
Clomiphene citrate 50 mg tab6.86USD tablet
Clomid 50 mg Tablet6.09USD tablet
Serophene 50 mg Tablet5.52USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)116.5-118Allen, R.E., Palopoli, F.P., Schumann, E.L. and Van Carnpen, M.G. Jr.; US. Patent 2,914,563; November 24, 1959; assigned to The Wrn. S. Merrell Company.
water solubilitySlightly solubleNot Available
logP7.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000414 mg/mLALOGPS
logP6.08ALOGPS
logP6.47Chemaxon
logS-6ALOGPS
pKa (Strongest Basic)9.31Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count2Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area12.47 Å2Chemaxon
Rotatable Bond Count9Chemaxon
Refractivity133.76 m3·mol-1Chemaxon
Polarizability46.72 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleYesChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.8723
Caco-2 permeable+0.7235
P-glycoprotein substrateSubstrate0.7536
P-glycoprotein inhibitor IInhibitor0.7799
P-glycoprotein inhibitor IINon-inhibitor0.6476
Renal organic cation transporterInhibitor0.7021
CYP450 2C9 substrateNon-substrate0.7972
CYP450 2D6 substrateNon-substrate0.6847
CYP450 3A4 substrateSubstrate0.7021
CYP450 1A2 substrateInhibitor0.9332
CYP450 2C9 inhibitorNon-inhibitor0.6036
CYP450 2D6 inhibitorInhibitor0.8315
CYP450 2C19 inhibitorInhibitor0.7004
CYP450 3A4 inhibitorNon-inhibitor0.8089
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9254
Ames testNon AMES toxic0.5
CarcinogenicityNon-carcinogens0.621
BiodegradationNot ready biodegradable0.9895
Rat acute toxicity1.8805 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.8038
hERG inhibition (predictor II)Inhibitor0.8672
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-MSsplash10-052r-9012000000-45df4fe468787edb6d89
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-0a4i-0000900000-6e563271338e3449b9f0
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0a4i-0000900000-6e563271338e3449b9f0
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0pb9-1700900000-a6f12bd1309cc00c965d
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9000100000-0006bfd0317a57de54bf
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0f89-9601100000-f4e27cfc7b768fe2877c
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0kcr-9215500000-bcd297fdc071ffc8f88d
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0ff0-9300000000-4dbfd23b04a5a8241370
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0540-7049000000-4b6a70ec6d2ec01ac700
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-207.1114728
predicted
DarkChem Lite v0.1.0
[M-H]-195.25578
predicted
DeepCCS 1.0 (2019)
[M+H]+206.6991728
predicted
DarkChem Lite v0.1.0
[M+H]+197.61378
predicted
DeepCCS 1.0 (2019)
[M+Na]+206.5472728
predicted
DarkChem Lite v0.1.0
[M+Na]+205.46138
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
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. Sasson S: Equilibrium binding analysis of estrogen agonists and antagonists: relation to the activation of the estrogen receptor. Pathol Biol (Paris). 1991 Jan;39(1):59-69. [Article]
  2. Kurosawa T, Hiroi H, Momoeda M, Inoue S, Taketani Y: Clomiphene citrate elicits estrogen agonistic/antagonistic effects differentially via estrogen receptors alpha and beta. Endocr J. 2010;57(6):517-21. Epub 2010 Apr 6. [Article]
  3. Hughes E, Brown J, Collins JJ, Vanderkerchove P: Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD000057. doi: 10.1002/14651858.CD000057.pub2. [Article]
  4. Brown J, Farquhar C, Beck J, Boothroyd C, Hughes E: Clomiphene and anti-oestrogens for ovulation induction in PCOS. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD002249. doi: 10.1002/14651858.CD002249.pub4. [Article]
  5. Authors unspecified: Use of clomiphene citrate in women. Fertil Steril. 2006 Nov;86(5 Suppl 1):S187-93. [Article]
  6. Overbeek A, Lambalk N: Pharmacogenomics of ovulation induction: facilitating decisions on who, when and how to treat. Pharmacogenomics. 2009 Sep;10(9):1377-9. doi: 10.2217/pgs.09.110. [Article]
  7. Homburg R: Oral agents for ovulation induction--clomiphene citrate versus aromatase inhibitors. Hum Fertil (Camb). 2008 Mar;11(1):17-22. doi: 10.1080/14647270701689670. [Article]
  8. Homburg R: Clomiphene citrate--end of an era? A mini-review. Hum Reprod. 2005 Aug;20(8):2043-51. Epub 2005 May 5. [Article]
  9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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. Hong H, Branham WS, Ng HW, Moland CL, Dial SL, Fang H, Perkins R, Sheehan D, Tong W: Human sex hormone-binding globulin binding affinities of 125 structurally diverse chemicals and comparison with their binding to androgen receptor, estrogen receptor, and alpha-fetoprotein. Toxicol Sci. 2015 Feb;143(2):333-48. doi: 10.1093/toxsci/kfu231. Epub 2014 Oct 27. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 17-alpha-monooxygenase activity
Specific Function
Conversion of pregnenolone and progesterone to their 17-alpha-hydroxylated products and subsequently to dehydroepiandrosterone (DHEA) and androstenedione. Catalyzes both the 17-alpha-hydroxylation ...
Gene Name
CYP17A1
Uniprot ID
P05093
Uniprot Name
Steroid 17-alpha-hydroxylase/17,20 lyase
Molecular Weight
57369.995 Da
References
  1. O'Keefe RK, Marrone BL: Inhibition of androgen and oestrogen production by clomiphene citrate in avian theca cells. J Reprod Fertil. 1986 Nov;78(2):541-8. doi: 10.1530/jrf.0.0780541. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Rao US, Fine RL, Scarborough GA: Antiestrogens and steroid hormones: substrates of the human P-glycoprotein. Biochem Pharmacol. 1994 Jul 19;48(2):287-92. [Article]

Drug created at June 13, 2005 13:24 / Updated at March 18, 2024 16:48