Identification

Summary

Flumazenil is a benzodiazepine antagonist that is used for the complete or partial reversal of the sedative effects caused by benzodiazepines in various clinical settings, such as induced general anesthesia for diagnostic and therapeutic procedures.

Generic Name
Flumazenil
DrugBank Accession Number
DB01205
Background

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.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 303.2884
Monoisotopic: 303.101919534
Chemical Formula
C15H14FN3O3
Synonyms
  • Flumazenil
  • Flumazenilo
  • Flumazenilum
  • Flumazepil
External IDs
  • Ro 15-1788
  • RO 15-1788/000
  • RO-15-1788
  • RO-151788
  • RO-1722
  • RO-41-8157
  • RO15-1788

Pharmacology

Indication

For 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.

Pharmacology
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Associated Conditions
Associated Therapies
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Flumazenil 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 action

Flumazenil, an imidazobenzodiazepine derivative, is a benzodiazepine antagonist. It competitively inhibits the benzodiazepine binding 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.

TargetActionsOrganism
AGamma-aminobutyric acid receptor subunit alpha-1
antagonist
Humans
AGamma-aminobutyric acid receptor subunit gamma-2
antagonist
Humans
AGamma-aminobutyric acid receptor subunit alpha-5
antagonist
Humans
AGABA(A) Receptor
positive allosteric modulator
Humans
Absorption

Not Available

Volume of distribution
  • 0.9 to 1.1 L/kg
Protein binding

Protein 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 elimination

Flumazenil 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-life

Initial 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]
Adverse Effects
Adverseeffects
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Toxicity

In clinical studies, most adverse reactions to flumazenil were an extension of the pharmacologic effects of the drug in reversing benzodiazepine effects.

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
AbacavirAbacavir may decrease the excretion rate of Flumazenil which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Flumazenil which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Flumazenil which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Flumazenil which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Flumazenil which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Flumazenil which could result in a higher serum level.
AclidiniumFlumazenil may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastineFlumazenil may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Flumazenil which could result in a higher serum level.
Adefovir dipivoxilAdefovir dipivoxil may decrease the excretion rate of Flumazenil which could result in a higher serum level.
Interactions
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Food Interactions
  • Take separate from meals. Eating during an intravenous infusion of flumazenil increases the elimination of flumazenil, potentially through elevated hepatic blood flow.

Products

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International/Other Brands
Anexate (Hoffmann-La Roche) / Lanexat / Mazicon
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Anexate Inj 0.1mg/mlSolution0.1 mg / mLIntravenousHoffmann La Roche1991-12-312012-05-24Canada flag
FlumazenilInjection0.1 mg/1mLIntravenousAkorn-Strides, LLC2008-05-13Not applicableUS flag
Flumazenil InjectionSolution0.1 mg / mLIntravenousFresenius Kabi2007-11-05Not applicableCanada flag
Flumazenil InjectionSolution0.1 mg / mLIntravenousSandoz Canada Incorporated2004-04-21Not applicableCanada flag
Flumazenil Injection SdzSolution0.1 mg / mLIntravenousSandoz Canada IncorporatedNot applicableNot applicableCanada flag
Flumazenil Injection, USPSolution0.1 mg / mLIntravenousMylan PharmaceuticalsNot applicableNot applicableCanada flag
RomaziconInjection, solution0.1 mg/1mLIntravenousGenentech, Inc.1991-12-202012-08-31US flag
RomaziconInjection, solution0.1 mg/1mLIntravenousGeneral Injectables & Vaccines2010-09-012017-01-18US flag
RomaziconInjection, solution0.1 mg/1mLIntravenousGenentech, Inc.1991-12-202013-01-31US flag
RomaziconInjection, solution0.1 mg/1mLIntravenousGeneral Injectables & Vaccines2010-08-012017-01-18US flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FlumazenilInjection, solution0.1 mg/1mLIntravenousFresenius Kabi USA, LLC2005-04-05Not applicableUS flag
FlumazenilInjection, solution0.1 mg/1mLIntravenousGeneral Injectables & Vaccines2013-03-132015-04-01US flag
FlumazenilInjection0.1 mg/1mLIntravenousMedical Purchasing Solutions, Llc2017-10-01Not applicableUS flag
FlumazenilInjection, solution0.1 mg/1mLIntravenousHF Acquisition Co LLC, DBA HealthFirst2021-06-28Not applicableUS flag
FlumazenilInjection0.1 mg/1mLIntravenousTeva Parenteral Medicines, Inc.2004-10-262012-03-31US flag
FlumazenilInjection, solution0.1 mg/1mLIntravenousWest-Ward Pharmaceuticals Corp2009-03-23Not applicableUS flag
FlumazenilInjection, solution0.1 mg/1mLIntravenousSina Health Inc2007-01-01Not applicableUS flag
FlumazenilInjection, solution0.1 mg/1mLIntravenousHikma Farmaceutica2007-01-012014-11-03US flag
FlumazenilInjection0.1 mg/1mLIntravenousBaxter Healthcare Corporation2017-10-01Not applicableUS flag
FlumazenilInjection, solution0.1 mg/1mLIntravenousMedical Purchasing Solutions, Llc2007-01-01Not applicableUS flag

Categories

ATC Codes
V03AB25 — Flumazenil
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzodiazepines
Sub Class
1,4-benzodiazepines
Direct Parent
Imidazo[1,5-a][1,4]benzodiazepines
Alternative Parents
1,4-diazepines / Carbonylimidazoles / Aryl fluorides / Benzenoids / N-substituted imidazoles / Vinylogous amides / Tertiary carboxylic acid amides / Heteroaromatic compounds / Carboxylic acid esters / Lactams
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Substituents
Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzenoid / Carboxamide group / Carboxylic acid derivative / Carboxylic acid ester / Heteroaromatic compound
show 18 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
organofluorine compound, ethyl ester, organic heterotricyclic compound, benzodiazepine (CHEBI:5103)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
40P7XK9392
CAS number
78755-81-4
InChI Key
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

References

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. [Article]
  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. [Article]
  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. [Article]
Human Metabolome Database
HMDB0015336
KEGG Drug
D00697
KEGG Compound
C07825
PubChem Compound
3373
PubChem Substance
46507438
ChemSpider
3256
BindingDB
26263
RxNav
4457
ChEBI
5103
ChEMBL
CHEMBL407
ZINC
ZINC000000001464
Therapeutic Targets Database
DAP000685
PharmGKB
PA449659
PDBe Ligand
FYP
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Flumazenil
PDB Entries
6d6t / 6d6u / 6x3u
FDA label
Download (244 KB)
MSDS
Download (51.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4TerminatedTreatmentHypoactive Delirium1
2CompletedTreatmentSubstance Related Disorders1
2TerminatedTreatmentObsessive Compulsive Disorder (OCD)1
2, 3CompletedTreatmentAlcohol Dependency1
1CompletedBasic ScienceAnxiety2
1CompletedTreatmentInsomnia1
1TerminatedBasic ScienceFragile X Syndrome (FXS) / Idiopathic Intellectual Developmental Disorder (IDD)1
1, 2CompletedOtherParkinson's Disease (PD)1
1, 2CompletedTreatmentAnxiety, Dental1
1, 2CompletedTreatmentHealthy Subjects (HS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Akorn Inc.
  • Apotex Inc.
  • APP Pharmaceuticals
  • A-S Medication Solutions LLC
  • Baxter International Inc.
  • Bedford Labs
  • Ben Venue Laboratories Inc.
  • F Hoffmann La Roche Ltd.
  • F Hoffmann-La Roche Ltd.
  • General Injectables and Vaccines Inc.
  • Hikma Pharmaceuticals
  • Physicians Total Care Inc.
  • Sandoz
  • Strides Arcolab Limited
  • Teva Pharmaceutical Industries Ltd.
  • West-Ward Pharmaceuticals
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous; Parenteral0.5 MG/5ML
Injection, solutionIntravenous; Parenteral1 MG/10ML
Injection, solutionParenteral
Injection, solutionIntravenous
SolutionIntravenous0.5 mg
InjectionIntravenous0.1 mg/1mL
InjectionIntravenous0.5 mg/5mL
InjectionIntravenous1 mg/10mL
Injection, solutionParenteral0.1 MG/ML
Injection, solution, concentrateIntravenous
Injection, solution
SolutionIntravenous0.1 mg / mL
Injection, solution, concentrateIntravenous; Parenteral0.1 MG/ML
Injection, solutionIntravenous0.1 mg/ml
SolutionIntravenous0.1 mg/ml
InjectionParenteral0.1 mg
Injection, solutionIntravenous0.1 mg/1mL
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.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)201-203 °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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0kdi-1293000000-7a192ee695af1d78e7bd
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0kdi-0193000000-a02a88da5dbc9ae8b8a5
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0lg0-3890000000-2453b74fd469fb228589

Targets

Drugtargets2
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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
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...
Gene Name
GABRA1
Uniprot ID
P14867
Uniprot Name
Gamma-aminobutyric acid receptor subunit alpha-1
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. [Article]
  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. [Article]
  3. Whitwam JG, Amrein R: Pharmacology of flumazenil. Acta Anaesthesiol Scand Suppl. 1995;108:3-14. [Article]
Kind
Protein
Organism
Humans
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...
Gene Name
GABRG2
Uniprot ID
P18507
Uniprot Name
Gamma-aminobutyric acid receptor subunit gamma-2
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. [Article]
  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. [Article]
  3. Whitwam JG, Amrein R: Pharmacology of flumazenil. Acta Anaesthesiol Scand Suppl. 1995;108:3-14. [Article]
Kind
Protein
Organism
Humans
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
Uniprot Name
Gamma-aminobutyric acid receptor subunit alpha-5
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. [Article]

Drug created at June 13, 2005 13:24 / Updated at December 01, 2021 01:05