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Identification
NameFlumazenil
Accession NumberDB01205  (APRD00974)
TypeSmall Molecule
GroupsApproved
Description

Fumazenil is an imidazobenzodiazepine derivative and a potent benzodiazepine receptor antagonist that competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex, thereby reversing the effects of benzodiazepine on the central nervous system.

Structure
Thumb
Synonyms
Anexate
Flumazenilo
Flumazenilum
Flumazepil
Lanexat
External Identifiers
  • Ro 15-1788
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Anexate Inj 0.1mg/mlsolution0.1 mgintravenousHoffmann La Roche Limited1991-12-312012-05-24Canada
Flumazenil Injectionsolution0.1 mgintravenousFresenius Kabi Canada Ltd2007-11-05Not applicableCanada
Flumazenil Injectionsolution0.1 mgintravenousSandoz Canada Incorporated2004-04-21Not applicableCanada
Flumazenil Injection Sdzsolution0.1 mgintravenousSandoz Canada IncorporatedNot applicableNot applicableCanada
Flumazenil Injection, USPsolution0.1 mgintravenousMylan Pharmaceuticals UlcNot applicableNot applicableCanada
Jamp-flumazenilsolution0.1 mgintravenousJamp Pharma CorporationNot applicableNot applicableCanada
Romaziconinjection, solution.1 mg/mLintravenousGeneral Injectables & Vaccines, Inc2010-09-01Not applicableUs
Romaziconinjection, solution.1 mg/mLintravenousGeneral Injectables & Vaccines, Inc2010-08-01Not applicableUs
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Flumazenilinjection.1 mg/mLintravenousPhysicians Total Care, Inc.2006-12-11Not applicableUs
Flumazenilinjection, solution.1 mg/mLintravenousGeneral Injectables & Vaccines, Inc2011-07-26Not applicableUs
Flumazenilinjection, solution.1 mg/mLintravenousPfizer Laboratories Div Pfizer Inc2011-05-10Not applicableUs
Flumazenilinjection, solution.1 mg/mLintravenousCardinal Health2007-01-01Not applicableUs
Flumazenilinjection.1 mg/mLintravenousGeneral Injectables and Vaccines, Inc2014-07-10Not applicableUs
Flumazenilinjection, solution.1 mg/mLintravenousSagent Pharmaceuticals2012-09-15Not applicableUs
Flumazenilinjection.1 mg/mLintravenousGENERAL INJECTABLES AND VACCINES, INC.2014-09-16Not applicableUs
Flumazenilinjection.1 mg/mLintravenousSandoz Inc2005-05-03Not applicableUs
Flumazenilinjection, solution.1 mg/mLintravenousWest Ward Pharmaceuticals Corp2007-01-01Not applicableUs
Flumazenilinjection, solution.1 mg/mLintravenousGeneral Injectables & Vaccines, Inc2010-03-01Not applicableUs
Flumazenilinjection.1 mg/mLintravenousWest Ward Pharmaceutical Corp.2004-10-12Not applicableUs
Flumazenilinjection, solution.1 mg/mLintravenousWest Ward Pharmaceuticals Corp2007-01-01Not applicableUs
Flumazenilinjection, solution.1 mg/mLintravenousGeneral Injectables & Vaccines, Inc2013-03-13Not applicableUs
Flumazenilinjection.1 mg/mLintravenousWest Ward Pharmaceutical Corp.2004-10-12Not applicableUs
Flumazenilinjection1 mg/10mLintravenousGeneral Injectables & Vaccines, Inc.2011-02-18Not applicableUs
Flumazenilinjection, solution.1 mg/mLintravenousWest ward Pharmaceutical Corp2009-03-23Not applicableUs
Flumazenilinjection, solution.1 mg/mLintravenousMylan Institutional LLC2011-05-10Not applicableUs
Flumazenilinjection.5 mg/5mLintravenousGeneral Injectables & Vaccines, Inc.2011-02-18Not applicableUs
Flumazenilinjection, solution.1 mg/mLintravenousWest ward Pharmaceutical Corp2009-03-23Not applicableUs
Flumazenilinjection, solution.1 mg/mLintravenousMylan Institutional LLC2011-05-10Not applicableUs
Flumazenilinjection, solution.1 mg/mLintravenousGeneral Injectables & Vaccines, Inc2013-03-13Not applicableUs
Flumazenilinjection, solution.1 mg/mLintravenousPfizer Laboratories Div Pfizer Inc2011-05-10Not applicableUs
Flumazenilinjection, solution.1 mg/mLintravenousAPP Pharmaceuticals, LLC2005-04-05Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
AnexateHoffmann-La Roche
LanexatNot Available
MaziconNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII40P7XK9392
CAS number78755-81-4
WeightAverage: 303.2884
Monoisotopic: 303.101919534
Chemical FormulaC15H14FN3O3
InChI KeyInChIKey=OFBIFZUFASYYRE-UHFFFAOYSA-N
InChI
InChI=1S/C15H14FN3O3/c1-3-22-15(21)13-12-7-18(2)14(20)10-6-9(16)4-5-11(10)19(12)8-17-13/h4-6,8H,3,7H2,1-2H3
IUPAC Name
ethyl 12-fluoro-8-methyl-9-oxo-2,4,8-triazatricyclo[8.4.0.0²,⁶]tetradeca-1(10),3,5,11,13-pentaene-5-carboxylate
SMILES
CCOC(=O)C1=C2CN(C)C(=O)C3=C(C=CC(F)=C3)N2C=N1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as imidazo[1,5-a][1,4]benzodiazepines. These are compounds containing an imidazole ring and a 1,4-benzodiazepine ring system, both sharing one nitrogen atom.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassBenzodiazepines
Sub Class1,4-benzodiazepines
Direct ParentImidazo[1,5-a][1,4]benzodiazepines
Alternative Parents
Substituents
  • Imidazo[1,5-a][1,4]benzodiazepine
  • Fluorobenzene
  • Para-diazepine
  • Benzenoid
  • N-substituted imidazole
  • Aryl halide
  • Aryl fluoride
  • Heteroaromatic compound
  • Vinylogous amide
  • Imidazole
  • Azole
  • Tertiary amine
  • Lactam
  • Carboxylic acid ester
  • Carboxamide group
  • Azacycle
  • Monocarboxylic acid or derivatives
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the complete or partial reversal of the sedative effects of benzodiazepines in cases where general anesthesia has been induced and/or maintained with benzodiazepines, and where sedation has been produced with benzodiazepines for diagnostic and therapeutic procedures. Also for the management of benzodiazepine overdose as an adjunct for appropriate supportive and symptomatic measures.
PharmacodynamicsFlumazenil antagonizes the CNS effects produced by benzodiazepines, but does not antagonize the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or general anesthetics) and does not reverse the effects of opioids.
Mechanism of actionFlumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in man.
Related Articles
AbsorptionNot Available
Volume of distribution
  • 0.9 to 1.1 L/kg
Protein bindingProtein binding is approximately 50%, mostly (66%) to albumin. Protein binding is reduced in patients with hepatic cirrhosis.
Metabolism

Hepatic. Flumazenil is completely (99%) metabolized. The major metabolites of flumazenil identified in urine are the de-ethylated free acid and its glucuronide conjugate.

Route of eliminationFlumazenil is completely (99%) metabolized. Elimination of radiolabeled drug is essentially complete within 72 hours, with 90% to 95% of the radioactivity appearing in urine and 5% to 10% in the feces.
Half lifeInitial distribution half-life is 4 to 11 minutes and the terminal half-life is 40 to 80 minutes. Prolongation of the half-life to 1.3 hours in patients with moderate hepatic impairment and 2.4 hours in severely impaired patients. Compared to adults, the elimination half-life in pediatric patients was more variable, averaging 40 minutes (range: 20 to 75 minutes).
Clearance
  • 1 L/hr/kg [healthy volunteers receiving a 5-minute infusion of a total of 1 mg]
ToxicityIn clinical studies, most adverse reactions to flumazenil were an extension of the pharmacologic effects of the drug in reversing benzodiazepine effects.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9937
Blood Brain Barrier+0.9382
Caco-2 permeable+0.5355
P-glycoprotein substrateSubstrate0.6137
P-glycoprotein inhibitor INon-inhibitor0.8502
P-glycoprotein inhibitor IINon-inhibitor0.8382
Renal organic cation transporterNon-inhibitor0.7508
CYP450 2C9 substrateNon-substrate0.8402
CYP450 2D6 substrateNon-substrate0.8404
CYP450 3A4 substrateSubstrate0.5764
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorInhibitor0.8995
CYP450 3A4 inhibitorNon-inhibitor0.866
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5863
Ames testNon AMES toxic0.6348
CarcinogenicityNon-carcinogens0.8872
BiodegradationNot ready biodegradable0.9928
Rat acute toxicity1.8903 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.987
hERG inhibition (predictor II)Non-inhibitor0.6394
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Injectionintravenous.1 mg/mL
Injectionintravenous.5 mg/5mL
Injectionintravenous1 mg/10mL
Injection, solutionintravenous.1 mg/mL
Solutionintravenous0.1 mg
Prices
Unit descriptionCostUnit
Romazicon 0.1 mg/ml vial25.14USD ml
Flumazenil 0.1 mg/ml vial1.63USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point201-203 °CPhysProp
water solubility128 mg/LNot Available
logP1.00MFG DATA SHEET
Predicted Properties
PropertyValueSource
Water Solubility1.04 mg/mLALOGPS
logP1.54ALOGPS
logP0.33ChemAxon
logS-2.5ALOGPS
pKa (Strongest Basic)3.27ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area64.43 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity87.93 m3·mol-1ChemAxon
Polarizability29.97 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Ngo AS, Anthony CR, Samuel M, Wong E, Ponampalam R: Should a benzodiazepine antagonist be used in unconscious patients presenting to the emergency department? Resuscitation. 2007 Jul;74(1):27-37. Epub 2007 Feb 15. [PubMed:17306436 ]
  2. Olkkola KT, Ahonen J: Midazolam and other benzodiazepines. Handb Exp Pharmacol. 2008;(182):335-60. doi: 10.1007/978-3-540-74806-9_16. [PubMed:18175099 ]
  3. Maeda S, Miyawaki T, Higuchi H, Shimada M: Effect of flumazenil on disturbance of equilibrium function induced by midazolam. Anesth Prog. 2008 Fall;55(3):73-7. doi: 10.2344/0003-3006-55.3.73. [PubMed:18788841 ]
External Links
ATC CodesV03AB25
AHFS Codes
  • 28:92.00
PDB EntriesNot Available
FDA labelDownload (244 KB)
MSDSDownload (51.1 KB)
Interactions
Drug Interactions
Drug
EszopicloneFlumazenil may decrease the sedative activities of Eszopiclone.
ZaleplonFlumazenil may decrease the sedative activities of Zaleplon.
ZolpidemFlumazenil may decrease the sedative activities of Zolpidem.
ZopicloneFlumazenil may decrease the sedative activities of Zopiclone.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Inhibitory extracellular ligand-gated ion channel activity
Specific Function:
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel (By si...
Gene Name:
GABRA1
Uniprot ID:
P14867
Molecular Weight:
51801.395 Da
References
  1. 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 ]
  2. Wingrove PB, Safo P, Wheat L, Thompson SA, Wafford KA, Whiting PJ: Mechanism of alpha-subunit selectivity of benzodiazepine pharmacology at gamma-aminobutyric acid type A receptors. Eur J Pharmacol. 2002 Feb 15;437(1-2):31-9. [PubMed:11864636 ]
  3. Whitwam JG, Amrein R: Pharmacology of flumazenil. Acta Anaesthesiol Scand Suppl. 1995;108:3-14. [PubMed:8693922 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Inhibitory extracellular ligand-gated ion channel activity
Specific Function:
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel.
Gene Name:
GABRG2
Uniprot ID:
P18507
Molecular Weight:
54161.78 Da
References
  1. Padgett CL, Lummis SC: The F-loop of the GABA A receptor gamma2 subunit contributes to benzodiazepine modulation. J Biol Chem. 2008 Feb 1;283(5):2702-8. Epub 2007 Oct 31. [PubMed:17974564 ]
  2. Wingrove PB, Safo P, Wheat L, Thompson SA, Wafford KA, Whiting PJ: Mechanism of alpha-subunit selectivity of benzodiazepine pharmacology at gamma-aminobutyric acid type A receptors. Eur J Pharmacol. 2002 Feb 15;437(1-2):31-9. [PubMed:11864636 ]
  3. Whitwam JG, Amrein R: Pharmacology of flumazenil. Acta Anaesthesiol Scand Suppl. 1995;108:3-14. [PubMed:8693922 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Transporter activity
Specific Function:
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
Gene Name:
GABRA5
Uniprot ID:
P31644
Molecular Weight:
52145.645 Da
References
  1. Clement Y, Le Guisquet AM, Venault P, Chapouthier G, Belzung C: Pharmacological alterations of anxious behaviour in mice depending on both strain and the behavioural situation. PLoS One. 2009 Nov 11;4(11):e7745. doi: 10.1371/journal.pone.0007745. [PubMed:19907641 ]
Kind
Protein group
Organism
Human
Pharmacological action
yes
Actions
positive allosteric modulator
General Function:
Inhibitory extracellular ligand-gated ion channel activity
Specific Function:
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel (By similarity).
Components:
NameUniProt IDDetails
Gamma-aminobutyric acid receptor subunit alpha-1P14867 Details
Gamma-aminobutyric acid receptor subunit alpha-2P47869 Details
Gamma-aminobutyric acid receptor subunit alpha-3P34903 Details
Gamma-aminobutyric acid receptor subunit alpha-4P48169 Details
Gamma-aminobutyric acid receptor subunit alpha-5P31644 Details
Gamma-aminobutyric acid receptor subunit alpha-6Q16445 Details
Gamma-aminobutyric acid receptor subunit beta-1P18505 Details
Gamma-aminobutyric acid receptor subunit beta-2P47870 Details
Gamma-aminobutyric acid receptor subunit beta-3P28472 Details
Gamma-aminobutyric acid receptor subunit deltaO14764 Details
Gamma-aminobutyric acid receptor subunit epsilonP78334 Details
Gamma-aminobutyric acid receptor subunit gamma-1Q8N1C3 Details
Gamma-aminobutyric acid receptor subunit gamma-2P18507 Details
Gamma-aminobutyric acid receptor subunit gamma-3Q99928 Details
Gamma-aminobutyric acid receptor subunit piO00591 Details
Gamma-aminobutyric acid receptor subunit thetaQ9UN88 Details
References
  1. ChEMBL Compound Report Card [Link]
Comments
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13