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
Structure for Remimazolam (DB12404)
- 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
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Maintenance of Procedural sedation •••••••••••• ••••• ••••••••• - Contraindications & Blackbox Warnings
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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
Target Actions Organism AGABA(A) Receptor positive allosteric modulatorHumans AGABA(A) Receptor Benzodiazepine Binding Site ligandHumans - 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
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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 Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The risk or severity of sedation can be increased when 1,2-Benzodiazepine is combined with Remimazolam. Acetazolamide The risk or severity of sedation can be increased when Acetazolamide is combined with Remimazolam. Acetophenazine The risk or severity of sedation can be increased when Acetophenazine is combined with Remimazolam. Agomelatine The risk or severity of CNS depression can be increased when Agomelatine is combined with Remimazolam. Alfentanil The risk or severity of sedation can be increased when Alfentanil is combined with Remimazolam. - Food Interactions
- Avoid alcohol. The sedative effects of benzodiazepines may be exacerbated by the co-administration of alcohol.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Remimazolam besylate 280XQ6482H 1001415-66-2 QMTKNJZIWGTNTE-LMOVPXPDSA-N Remimazolam tosylate 9J7J08A8LT 1425904-79-5 UNLWPYSYFQLJSV-LMOVPXPDSA-N - International/Other Brands
- Byfavo
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Byfavo Injection, powder, lyophilized, for solution 2.5 mg/1mL Intravenous Acacia Pharma, Ltd. 2020-10-06 Not applicable US 
Byfavo Injection, powder, for solution 20 mg Intravenous Paion Deutschland Gmb H 2021-04-25 Not applicable EU 
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
- 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]
- 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]
- 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]
- Egan TD: Is anesthesiology going soft?: trends in fragile pharmacology. Anesthesiology. 2009 Aug;111(2):229-30. doi: 10.1097/ALN.0b013e3181ae8460. [Article]
- 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]
- FDA Approved Drug Products: Byfavo (remimazolam) for intravenous injection [Link]
- Cosmo Pharmaceuticals: Cosmo Pharmaceuticals Announces US FDA Approval of BYFAVO (remimazolam injection) [Link]
- FDA Approved Drug Products: Byfavo (remimazolam) for intravenous injection [Updated 01/2023] [Link]
- External Links
- Human Metabolome Database
- HMDB0304851
- PubChem Compound
- 9867812
- PubChem Substance
- 347828650
- ChemSpider
- 8043503
- 2383941
- ChEMBL
- CHEMBL4297526
- ZINC
- ZINC000003927450
- Wikipedia
- Remimazolam
- FDA label
- Download (713 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Active Not Recruiting Treatment Anesthesia therapy / Hepatic Failure / Intensive Care Units (ICUs) / Mechanical Ventilation / Pharmacokinetics 1 4 Completed Other Hypotension During Surgery 1 4 Completed Prevention Benzodiazepines / High Risk Patients / Post Operative Nausea and Vomiting (PONV) 1 4 Completed Prevention Midazolam / Remimazolam / Sedation Complication 1 4 Completed Screening Hypothermia; Anesthesia 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, powder, for solution Intravenous 20 mg Injection, powder, lyophilized, for solution Intravenous 2.5 mg/1mL Powder Intravenous 50 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9914738 No 2018-03-13 2027-07-10 US US9777007 No 2017-10-03 2027-07-10 US US10472365 No 2019-11-12 2027-07-10 US US9827251 No 2017-11-28 2031-11-07 US US9737547 No 2017-08-22 2031-11-07 US US10052334 No 2018-08-21 2031-11-07 US US10195210 No 2019-02-05 2031-11-07 US US10342800 No 2019-07-09 2031-11-07 US US9561236 No 2017-02-07 2033-04-30 US US10722522 No 2020-07-28 2031-11-07 US US10961250 No 2021-03-30 2027-07-10 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Sparingly soluble FDA Label - Predicted Properties
Property Value Source Water Solubility 0.0213 mg/mL ALOGPS logP 3.68 ALOGPS logP 3.75 Chemaxon logS -4.3 ALOGPS pKa (Strongest Basic) 5.99 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 69.37 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 119.71 m3·mol-1 Chemaxon Polarizability 43.12 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-000i-0000900000-ec1fc3232f381ec63a2c Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-000i-1001900000-b6bdb0c2a78df836e592 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0a70-6026900000-b14f80b295b7b2a7d8c0 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-000i-0000900000-6e4cf7452054e4784f37 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00kr-1029200000-4e94c30c95ba589a3fe9 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-002f-9020000000-e83bb14e86891cf48923 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 183.89934 predictedDeepCCS 1.0 (2019) [M+H]+ 186.25734 predictedDeepCCS 1.0 (2019) [M+Na]+ 193.09355 predictedDeepCCS 1.0 (2019)
Targets
- 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
- 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]
- 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]
- 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
- 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]
- 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]
- 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
- 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]
- 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
- FDA Approved Drug Products: Byfavo (remimazolam) for intravenous injection [Link]
Drug created at October 20, 2016 22:15 / Updated at February 02, 2023 07:21