Identification

Name
Flumazenil
Accession Number
DB01205  (APRD00974)
Type
Small Molecule
Groups
Approved
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
  • Flumazenilo
  • Flumazenilum
  • Flumazepil
External IDs
Ro 15-1788 / RO 15-1788/000 / RO-15-1788 / RO-151788 / RO-1722 / RO-41-8157 / RO15-1788
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Anexate Inj 0.1mg/mlSolution0.1 mgIntravenousHoffmann La Roche1991-12-312012-05-24Canada
FlumazenilInjection0.1 mg/1mLIntravenousAkorn-Strides, LLC2008-05-13Not applicableUs
Flumazenil InjectionSolution0.1 mgIntravenousFresenius Kabi2007-11-05Not applicableCanada
Flumazenil InjectionSolution0.1 mgIntravenousSandoz Canada Incorporated2004-04-21Not applicableCanada
Flumazenil Injection SdzSolution0.1 mgIntravenousSandoz Canada IncorporatedNot applicableNot applicableCanada
Flumazenil Injection, USPSolution0.1 mgIntravenousMylan PharmaceuticalsNot applicableNot applicableCanada
RomaziconInjection, solution0.1 mg/1mLIntravenousGeneral Injectables & Vaccines2010-08-012017-01-18Us
RomaziconInjection, solution0.1 mg/1mLIntravenousGenentech, Inc.1991-12-202012-08-31Us
RomaziconInjection, solution0.1 mg/1mLIntravenousGeneral Injectables & Vaccines2010-09-012017-01-18Us
RomaziconInjection, solution0.1 mg/1mLIntravenousGenentech, Inc.1991-12-202013-01-31Us
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
FlumazenilInjection, solution0.1 mg/1mLIntravenousMylan Institutional2011-05-10Not applicableUs
FlumazenilInjection0.1 mg/1mLIntravenousTeva Parenteral Medicines, Inc.2004-10-262012-03-31Us
FlumazenilInjection, solution0.1 mg/1mLIntravenousMedical Purchasing Solutions, Llc2007-01-01Not applicableUs
FlumazenilInjection, solution0.1 mg/1mLIntravenousGeneral Injectables and Vaccines, Inc.2014-09-16Not applicableUs
FlumazenilInjection, solution0.1 mg/1mLIntravenousSagent Pharmaceuticals2012-09-152018-10-24Us
FlumazenilInjection, solution0.1 mg/1mLIntravenousCardinal Health2007-01-01Not applicableUs
FlumazenilInjection, solution0.1 mg/1mLIntravenousGeneral Injectables & Vaccines2013-03-132015-05-01Us
FlumazenilInjection, solution0.1 mg/1mLIntravenousHikma Farmaceutica2007-01-012014-11-03Us
FlumazenilInjection0.1 mg/1mLIntravenousBaxter Healthcare Corporation2017-10-01Not applicableUs
FlumazenilInjection, solution0.1 mg/1mLIntravenousWest Ward Pharmaceutical2009-03-23Not applicableUs
International/Other Brands
Anexate (Hoffmann-La Roche) / Lanexat / Mazicon
Categories
UNII
40P7XK9392
CAS number
78755-81-4
Weight
Average: 303.2884
Monoisotopic: 303.101919534
Chemical Formula
C15H14FN3O3
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

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.

Associated Conditions
Associated Therapies
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, 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.

TargetActionsOrganism
AGamma-aminobutyric acid receptor subunit alpha-1
antagonist
Human
AGamma-aminobutyric acid receptor subunit gamma-2
antagonist
Human
AGamma-aminobutyric acid receptor subunit alpha-5
antagonist
Human
AGABA-A receptor (anion channel)
positive allosteric modulator
Human
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]
Toxicity

In 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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Flumazenil which could result in a higher serum level.
AcarboseAcarbose 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.
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.
AdefovirAdefovir may decrease the excretion rate of Flumazenil which could result in a higher serum level.
Food Interactions
Not Available

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. [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
Human Metabolome Database
HMDB0015336
KEGG Drug
D00697
KEGG Compound
C07825
PubChem Compound
3373
PubChem Substance
46507438
ChemSpider
3256
BindingDB
26263
ChEBI
5103
ChEMBL
CHEMBL407
Therapeutic Targets Database
DAP000685
PharmGKB
PA449659
HET
FYP
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Flumazenil
ATC Codes
V03AB25 — Flumazenil
AHFS Codes
  • 28:92.00 — Miscellaneous Central Nervous System Agents
PDB Entries
6d6t / 6d6u
FDA label
Download (244 KB)
MSDS
Download (51.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentSleeplessness1
1, 2CompletedTreatmentDental Anxiety1
1, 2CompletedTreatmentHealthy Volunteers1
1, 2CompletedTreatmentHypersomnia / Idiopathic Hypersomnia / Narcolepsy Without Cataplexy / Primary Hypersomnia1
1, 2RecruitingOtherParkinson's Disease (PD)1
1, 2RecruitingTreatmentBrain Injury1
1, 2WithdrawnBasic ScienceHepatic Encephalopathy / Liver Cirrhosis1
2CompletedTreatmentSubstance-Related Disorders1
2TerminatedTreatmentObsessive Compulsive Disorder (OCD)1
2, 3CompletedTreatmentAlcohol Dependence1
4RecruitingTreatmentDelirium1
Not AvailableCompletedNot AvailableAdverse Effect of Other General Anesthetics1
Not AvailableCompletedBasic ScienceAcupuncture / General Anaesthesia / Sedation therapy1

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
InjectionIntravenous0.1 mg/1mL
InjectionIntravenous0.5 mg/5mL
InjectionIntravenous1 mg/10mL
SolutionIntravenous0.1 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

Taxonomy

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
show 8 more
Substituents
Imidazo[1,5-a][1,4]benzodiazepine / Para-diazepine / Imidazole-4-carbonyl group / Aryl fluoride / Aryl halide / Benzenoid / N-substituted imidazole / Azole / Heteroaromatic compound / Vinylogous amide
show 18 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
organofluorine compound, ethyl ester, organic heterotricyclic compound, benzodiazepine (CHEBI:5103)

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...
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. [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...
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. [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
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. [PubMed:19907641]

Drug created on June 13, 2005 07:24 / Updated on November 14, 2018 12:50