Remimazolam

Identification

Summary

Remimazolam is an ultra short-acting benzodiazepine used for the induction and maintenence of procedural sedation during short procedures.

Brand Names
Byfavo
Generic Name
Remimazolam
DrugBank Accession Number
DB12404
Background

Remimazolam is an ultra short-acting benzodiazepine used in the induction and maintenance of sedation during short (<30 minute) procedures.6 Recent trends in anesthesia-related drug development have touted the benefits of so-called "soft drugs" - these agents, such as remifentanil, are designed to be metabolically fragile and thus susceptible to rapid biotransformation and elimination as inactive metabolites.4 These "soft drugs" are useful in the context of surgical procedures, wherein a rapid onset/offset is desirable, enabling anesthesiologists to manipulate drug concentrations as needed.3,4 Remimazolam was the first "soft" benzodiazepine analog to be developed5 and was approved for use by the FDA in July 2020 under the brand name Byfavo.7

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 439.313
Monoisotopic: 438.069139
Chemical Formula
C21H19BrN4O2
Synonyms
  • Remimazolam
External IDs
  • CNS 7056
  • CNS-7056
  • CNS7056
  • ONO-2745
  • WHO 9232

Pharmacology

Indication

Remimazolam is indicated for the induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less.6

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Remimazolam modulates the effects of GABA(A) receptors in order to enhance the effects of GABA. It is considered an "ultra short-acting" benzodiazepine1 that achieves peak sedation within 3 to 3.5 minutes following intravenous administration,6 a property that makes it desirable for use during short procedures. Hepatic impairment can result in elevated serum levels of remimazolam - patients with severe hepatic impairment should be carefully titrated to effect.6 As of its approval date, remimazolam has not received a scheduling action by the DEA under the Controlled Substances Act. As benzodiazepines as a class have been implicated in the development of drug dependence and have a known potential for abuse, remimazolam should be used with caution in patients with a history of drug dependence or abuse.6

Mechanism of action

Like other benzodiazepines, remimazolam exerts its therapeutic effects by potentiating the effect of gamma-aminobutyric acid (GABA) on GABA(A) receptors, the main inhibitory neurotransmitter receptors in the mammalian brain.2 GABA(A) receptors are a component of GABA-gated ionotropic chloride channels that produce inhibitory postsynaptic potentials - following activation by GABA, the channel undergoes a conformational change that allows the passage of chloride ions through the channel. The inhibitory potentials produced by GABA neurotransmission play an integral role in the suppression and control of epileptiform nerve firing such as that seen in epilepsy, which makes the GABA system a desirable target in the treatment of epilepsy.

Benzodiazepines are positive allosteric modulators of GABA(A) function. They bind to the interface between alpha (α) and gamma (γ) subunits on the receptor, commonly referred to as the benzodiazepine binding site, and modulate the receptor such that its inhibitory response to GABA binding is dramatically increased.2

TargetActionsOrganism
AGABA(A) Receptor
positive allosteric modulator
Humans
AGABA(A) Receptor Benzodiazepine Binding Site
ligand
Humans
Absorption

The Cmax and AUC0-inf following intravenous administration of 0.01 to 0.5 mg/kg were 189 to 6,960 ng/mL and 12.1 to 452 ng∙h/mL, respectively,6 and appear to be relatively dose proportional. The Tmax of the inactive CNS7054 metabolite is approximately 20-30 minutes and its AUC0-inf ranges from 231 to 7,090 ng∙h/mL.6

Volume of distribution

The volume of distribution is approximately 0.76 - 0.98 L/kg.6

Protein binding

Remimazolam is >91% protein-bound in plasma, primarily to serum albumin.6

Metabolism

Remimazolam does not appear to undergo biotransformation via hepatic cytochrome P450 enzymes, nor does it induce or inhibit these enzymes.6 Its primary route of metabolism is hydrolysis via hepatic carboxylesterase-1 (CES1) to yield the inactive CNS7054 metabolite, which then undergoes glucuronidation and hydroxylation prior to elimination.6,1 CNS7054 possesses a 300-fold lesser affinity for GABA(A) receptors as compared to the parent drug.

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Route of elimination

In patients undergoing colonoscopy, approximately 0.003% of the administered dose is excreted in the urine as unchanged parent drug and 50-60% is excreted in the urine as CNS7054.6 In healthy subjects, >80% of the administered dose is excreted in the urine as CNS7054.6

Half-life

Following intravenous administration, the distribution half-life is of remimazolam is 0.5 - 2 minutes and the terminal elimination half-life is 37 - 53 minutes.6 Half-life is increased in patients with hepatic impairment necessitating careful dose titration in this population.6 The half-life of remimazolam's major inactive metabolite, CNS7054, is 2.4 - 3.8 hours.6

Clearance

The clearance of remimazolam is approximately 24 - 75 L/h and is independent of body weight.6

Adverse Effects
Adverseeffects
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Toxicity

Symptoms of remimazolam overdoses, as with other benzodiazepines, are likely to be consistent with its adverse effect profile and may therefore involve significant CNS depression, respiratory depression, ataxia, and hypotension.6 The benzodiazepine receptor antagonist flumazenil may be used for reversal of the sedative effects associated with benzodiazepine overdose, though it is not a substitute for proper supportive care.6

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
1,2-BenzodiazepineThe risk or severity of sedation can be increased when 1,2-Benzodiazepine is combined with Remimazolam.
AcetazolamideThe risk or severity of sedation can be increased when Acetazolamide is combined with Remimazolam.
AcetophenazineThe risk or severity of sedation can be increased when Acetophenazine is combined with Remimazolam.
AclidiniumRemimazolam may increase the central nervous system depressant (CNS depressant) activities of Aclidinium.
AgomelatineThe risk or severity of adverse effects can be increased when Agomelatine is combined with Remimazolam.
AlfentanilThe risk or severity of sedation can be increased when Alfentanil is combined with Remimazolam.
AlimemazineThe risk or severity of adverse effects can be increased when Alimemazine is combined with Remimazolam.
AlmotriptanThe risk or severity of adverse effects can be increased when Almotriptan is combined with Remimazolam.
AlosetronThe risk or severity of adverse effects can be increased when Alosetron is combined with Remimazolam.
AlprazolamThe risk or severity of adverse effects can be increased when Alprazolam is combined with Remimazolam.
Interactions
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Food Interactions
  • Avoid alcohol. The sedative effects of benzodiazepines may be exacerbated by the co-administration of alcohol.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Remimazolam besylate280XQ6482H1001415-66-2QMTKNJZIWGTNTE-LMOVPXPDSA-N
Remimazolam tosylate9J7J08A8LT1425904-79-5UNLWPYSYFQLJSV-LMOVPXPDSA-N
International/Other Brands
Byfavo
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ByfavoInjection, powder, for solution20 mgIntravenousPaion Netherlands B.V.2021-04-25Not applicableEU flag
ByfavoInjection, powder, lyophilized, for solution2.5 mg/1mLIntravenousAcacia Pharma, Ltd.2020-10-06Not applicableUS flag

Categories

ATC Codes
N05CD14 — Remimazolam
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as 1,4-benzodiazepines. These are organic compounds containing a benzene ring fused to a 1,4-azepine.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzodiazepines
Sub Class
1,4-benzodiazepines
Direct Parent
1,4-benzodiazepines
Alternative Parents
Fatty acid esters / Pyridines and derivatives / Aryl bromides / Benzenoids / N-substituted imidazoles / Heteroaromatic compounds / Methyl esters / Ketimines / Azacyclic compounds / Propargyl-type 1,3-dipolar organic compounds
show 6 more
Substituents
1,4-benzodiazepine / Aromatic heteropolycyclic compound / Aryl bromide / Aryl halide / Azacycle / Azole / Benzenoid / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
7V4A8U16MB
CAS number
308242-62-8
InChI Key
CYHWMBVXXDIZNZ-KRWDZBQOSA-N
InChI
InChI=1S/C21H19BrN4O2/c1-13-12-24-21-17(7-9-19(27)28-2)25-20(16-5-3-4-10-23-16)15-11-14(22)6-8-18(15)26(13)21/h3-6,8,10-12,17H,7,9H2,1-2H3/t17-/m0/s1
IUPAC Name
methyl 3-[(7S)-12-bromo-3-methyl-9-(pyridin-2-yl)-2,5,8-triazatricyclo[8.4.0.0^{2,6}]tetradeca-1(14),3,5,8,10,12-hexaen-7-yl]propanoate
SMILES
COC(=O)CC[C@@H]1N=C(C2=CC=CC=N2)C2=CC(Br)=CC=C2N2C(C)=CN=C12

References

Synthesis Reference

Dolitzky Ben-Zion, Mendelovici Marioara, Bodkhe Arjun Rajaram, Mane Ganesh Shivaji, Samala Rajamouli Srihari, Joshi Ashutosh Vijay, Parven Kumar Luthra, Amit Singh, Anantha Rajmohan Muthusamy "Process for the preparation of remimazolam and solid state forms of remimazolam salts." U.S. Patent US20190359619A1, filed Feb, 2018.

General References
  1. Freyer N, Knospel F, Damm G, Greuel S, Schneider C, Seehofer D, Stohr T, Petersen KU, Zeilinger K: Metabolism of remimazolam in primary human hepatocytes during continuous long-term infusion in a 3-D bioreactor system. Drug Des Devel Ther. 2019 Apr 2;13:1033-1047. doi: 10.2147/DDDT.S186759. eCollection 2019. [Article]
  2. Sigel E, Steinmann ME: Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012 Nov 23;287(48):40224-31. doi: 10.1074/jbc.R112.386664. Epub 2012 Oct 4. [Article]
  3. Birgenheier NM, Stuart AR, Egan TD: Soft drugs in anesthesia: remifentanil as prototype to modern anesthetic drug development. Curr Opin Anaesthesiol. 2020 Jun 8. doi: 10.1097/ACO.0000000000000879. [Article]
  4. Egan TD: Is anesthesiology going soft?: trends in fragile pharmacology. Anesthesiology. 2009 Aug;111(2):229-30. doi: 10.1097/ALN.0b013e3181ae8460. [Article]
  5. Goudra BG, Singh PM: Remimazolam: The future of its sedative potential. Saudi J Anaesth. 2014 Jul;8(3):388-91. doi: 10.4103/1658-354X.136627. [Article]
  6. FDA Approved Drug Products: Byfavo (remimazolam) for intravenous injection [Link]
  7. Cosmo Pharmaceuticals: Cosmo Pharmaceuticals Announces US FDA Approval of BYFAVO (remimazolam injection) [Link]
PubChem Compound
9867812
PubChem Substance
347828650
ChemSpider
8043503
RxNav
2383941
ChEMBL
CHEMBL4297526
ZINC
ZINC000003927450
Wikipedia
Remimazolam
FDA label
Download (713 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Not Yet RecruitingOtherAnaesthesia therapy1
4Not Yet RecruitingOtherHypotension During Surgery1
4Not Yet RecruitingPreventionMidazolam / Remimazolam / Sedation Complication1
4Not Yet RecruitingSupportive CareSedation1
4RecruitingPreventionBenzodiazepines / Bladder Cancer, Cancer / Cancer Recurrence / Delirium / Surgery1
4RecruitingPreventionBenzodiazepines / High Risk Patients / Post Operative Nausea and Vomiting (PONV)1
4RecruitingPreventionEmergence Delirium1
4RecruitingTreatmentBronchoscopy; / Sedation1
4RecruitingTreatmentSedative; Anxiety Disorder1
3CompletedOtherSedation2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous20 MG
Injection, powder, lyophilized, for solutionIntravenous2.5 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9914738No2007-07-102027-07-10US flag
US9777007No2007-07-102027-07-10US flag
US10472365No2007-07-102027-07-10US flag
US9827251No2011-11-072031-11-07US flag
US9737547No2011-11-072031-11-07US flag
US10052334No2011-11-072031-11-07US flag
US10195210No2011-11-072031-11-07US flag
US10342800No2011-11-072031-11-07US flag
US9561236No2013-04-302033-04-30US flag
US10722522No2011-11-072031-11-07US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySparingly solubleFDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.0213 mg/mLALOGPS
logP3.68ALOGPS
logP3.75ChemAxon
logS-4.3ALOGPS
pKa (Strongest Basic)5.99ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area69.37 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity119.71 m3·mol-1ChemAxon
Polarizability43.12 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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

Targets

Drugtargets2
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Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Positive allosteric modulator
Curator comments
The GABA(A) receptor is pentameric (i.e. comprising 5 subunit proteins) and therefore has a multitude of potential isoforms. The above target is a collection of all possible GABA(A) subunits that may participate in the formation of the pentameric receptor and is not meant to imply direct a drug-protein interaction for each individual subunit.
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...

Components:
References
  1. Sigel E, Steinmann ME: Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012 Nov 23;287(48):40224-31. doi: 10.1074/jbc.R112.386664. Epub 2012 Oct 4. [Article]
  2. Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE: Structure of a human synaptic GABAA receptor. Nature. 2018 Jul;559(7712):67-72. doi: 10.1038/s41586-018-0255-3. Epub 2018 Jun 27. [Article]
  3. FDA Approved Drug Products: Byfavo (remimazolam) for intravenous injection [Link]
Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Ligand
Curator comments
Benzodiazepines modulate GABA(A) function by binding at the interface between alpha (α) and gamma (γ) subunits. Of the 6 α-subunits, only 4 (α-1, -2, -3, and -5) participate in the formation of this binding site. The above target is a collection of all α- and γ-subunits that are known to participate in the formation of the benzodiazepine binding site.
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...

Components:
References
  1. Sigel E, Steinmann ME: Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012 Nov 23;287(48):40224-31. doi: 10.1074/jbc.R112.386664. Epub 2012 Oct 4. [Article]
  2. Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE: Structure of a human synaptic GABAA receptor. Nature. 2018 Jul;559(7712):67-72. doi: 10.1038/s41586-018-0255-3. Epub 2018 Jun 27. [Article]
  3. FDA Approved Drug Products: Byfavo (remimazolam) for intravenous injection [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Triglyceride lipase activity
Specific Function
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acy...
Gene Name
CES1
Uniprot ID
P23141
Uniprot Name
Liver carboxylesterase 1
Molecular Weight
62520.62 Da
References
  1. Freyer N, Knospel F, Damm G, Greuel S, Schneider C, Seehofer D, Stohr T, Petersen KU, Zeilinger K: Metabolism of remimazolam in primary human hepatocytes during continuous long-term infusion in a 3-D bioreactor system. Drug Des Devel Ther. 2019 Apr 2;13:1033-1047. doi: 10.2147/DDDT.S186759. eCollection 2019. [Article]
  2. FDA Approved Drug Products: Byfavo (remimazolam) for intravenous injection [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. FDA Approved Drug Products: Byfavo (remimazolam) for intravenous injection [Link]

Drug created on October 20, 2016 22:15 / Updated on February 21, 2021 18:53