Remimazolam

Remimazolam
Names
Trade namesByfavo
Other namesRemimazolam besylate, CNS-7056[1]
IUPAC name
  • methyl 3-[(4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate
Clinical data
Drug classBenzodiazepine[2]
Main usesProcedural sedation[3]
Side effectsLow blood pressure, high blood pressure, low oxygen[3]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Routes of
use		Intravenous
Duration of action10 min[4]
External links
AHFS/Drugs.comMonograph
Legal
License data
Legal status
Chemical and physical data
FormulaC21H19BrN4O2
Molar mass439.313 g·mol−1
3D model (JSmol)
SMILES
  • COC(=O)CC[C@@H]1N=C(c2ccccn2)c2cc(Br)ccc2-n2c(C)cnc21
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 ☒N
  • Key:CYHWMBVXXDIZNZ-KRWDZBQOSA-N ☒N

Remimazolam, sold under the brand name Byfavo, is a medication used for procedural sedation.[3] Specifically it is used in adults for procedures lasting less than 30 minutes.[3] It is given by injection into a vein.[3] While onset of effects is similar, the duration is shorter than midazolam.[5][6]

Common side effects include low blood pressure, high blood pressure, and low oxygen.[3] Other side effects may include abuse and allergic reactions.[3] Effectiveness is not altered in kidney problems, though lower doses may be used in those with liver problems.[3][7] Effects can be revered with flumazenil.[4] It is a benzodiazepine and works by attaching to gamma-amino butyric acid (GABA) receptors.[2]

Remimazolam was approved for medical use in the United States in 2020 and Europe in 2021.[3][2] In the United States a vial of 20 mg costs about 42 USD as of 2022.[8]

Medical uses

Remimazolam is indicated for the induction and maintenance of procedural sedation in adults lasting 30 minutes or less.[9][10]

Dosage

It is generally given as an initial dose of 5 mg over a minute.[3] Further doses of 2.5 mg over 15 seconds may be given after 2 minutes.[3]

History

Remimazolam was approved for medical use in the United States in July 2020.[9]

The U.S. Food and Drug Administration (FDA) approved remimazolam based on evidence from three clinical trials (Trial 1/NCT02290873, Trial 2/NCT02296892 and Trial 3/NCT02532647) in adults undergoing short procedures.[9] Trials were conducted at 32 sites in the United States.[9]

Trials 1 and 3 were conducted in participants undergoing colonoscopy and Trial 2 was conducted in participants undergoing bronchoscopy procedures.[9]

In the trials, participants were randomly divided in three groups: one group received remimazolam, one group received placebo and one group received midazolam (similar, but approved drug).[9] In the first two groups, neither participants nor investigators knew which medications were given and participants could also receive midazolam as a rescue drug when needed for sedation.[9] In the third group, all participants received midazolam only[9] Additionally, in all three trials participants received a medication for pain control[9]

Trials 1 and 2 compared participants who received remimazolam to participants in the other two groups, measuring the success of sedation with the set of pre-determined criteria.[9] Data from Trial 3 were used primarily to assess the side effects of remimazolam when multiple dosing is used.[9]

Society and culture

On 28 January 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Byfavo, intended for procedural sedation.[11] The applicant for this medicinal product is PAION Netherlands B.V.[11] Remimazolam (Byfavo) was approved for medical use in the European Union in March 2021.[2]

Research

Phase I[12] and Ib[13] dose-finding studies for procedural sedation with patients recovering faster from remimazolam than midazolam. Phase II trials comparing remimazolam to the standard anesthesia protocols for cardiac surgery and colonoscopy were presented at major conferences in October 2014.[14]

A Phase IIa trial comparing remimazolam to midazolam for upper endoscopy was published in December 2014, finding a similar safety profile.[15] Remimazolam was originally synthesized in the late 1990s at Glaxo Wellcome in their labs in Research Triangle Park, North Carolina.[16][17][18]

References

  1. ↑ Kilpatrick GJ, McIntyre MS, Cox RF, Stafford JA, Pacofsky GJ, Lovell GG, et al. (2007). "CNS 7056: a novel ultra-short-acting Benzodiazepine". Anesthesiology. 107 (1): 60–6. doi:10.1097/01.anes.0000267503.85085.c0. PMID 17585216. S2CID 19504961.
  2. 1 2 3 4 5 "Byfavo EPAR". European Medicines Agency (EMA). 9 December 2020. Archived from the original on 21 April 2021. Retrieved 20 April 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 "Byfavo- remimazolam besylate injection, powder, lyophilized, for solution". DailyMed. 20 July 2020. Archived from the original on 22 October 2022. Retrieved 25 February 2021.
  4. 1 2 Kaye, Alan David (5 June 2017). Pharmacology, An Issue of Anesthesiology Clinics. Elsevier Health Sciences. p. e101. ISBN 978-0-323-52998-3. Archived from the original on 12 November 2022. Retrieved 3 November 2022.
  5. ↑ Noor, N; Legendre, R; Cloutet, A; Chitneni, A; Varrassi, G; Kaye, AD (2021). "A comprehensive review of remimazolam for sedation". Health psychology research. 9 (1): 24514. doi:10.52965/001c.24514. PMID 34746482.
  6. ↑ Goudra, BG; Singh, PM (July 2014). "Remimazolam: The future of its sedative potential". Saudi journal of anaesthesia. 8 (3): 388–91. doi:10.4103/1658-354X.136627. PMID 25191193.
  7. ↑ "Remimazolam Monograph for Professionals". Drugs.com. Retrieved 3 November 2022.
  8. ↑ "Byfavo Prices, Coupons, Copay & Patient Assistance". Drugs.com. Archived from the original on 29 May 2022. Retrieved 3 November 2022.
  9. 1 2 3 4 5 6 7 8 9 10 11 "Drug Trials Snapshots: Byfavo". Food and Drug Administration. 2 July 2020. Archived from the original on 7 March 2021. Retrieved 25 February 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  10. ↑ "Byfavo: FDA-Approved Drugs". Food and Drug Administration. Archived from the original on 21 March 2021. Retrieved 25 February 2021.
  11. 1 2 "Byfavo: Pending EC decision". European Medicines Agency. 29 January 2021. Archived from the original on 22 February 2021. Retrieved 25 February 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  12. ↑ Antonik LJ, Goldwater DR, Kilpatrick GJ, Tilbrook GS, Borkett KM (2012). "A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part I. Safety, efficacy, and basic pharmacokinetics". Anesthesia and Analgesia. 115 (2): 274–83. doi:10.1213/ANE.0b013e31823f0c28. PMID 22190555. S2CID 21457057.
  13. ↑ Worthington, Mark T.; Antonik, Laurie J.; Goldwater, D. Ronald; Lees, James P.; Wilhelm-Ogunbiyi, Karin; Borkett, Keith M.; Mitchell, Mack C. (2013). "A phase Ib, dose-finding study of multiple doses of remimazolam (CNS 7056) in volunteers undergoing colonoscopy". Anesthesia & Analgesia. 117 (5): 1093–100. doi:10.1213/ANE.0b013e3182a705ae. PMID 24108261. S2CID 24581168.
  14. ↑ "Two Scientific Remimazolam Presentations Are Accepted for ASA and ACG Meeting in October 2014". MarketWired. Oct 1, 2014. Archived from the original on 4 March 2016. Retrieved 25 February 2021.
  15. ↑ Borkett KM, Riff DS, Schwartz HI, Winkle PJ, Pambianco DJ, Lees JP, et al. (2015). "A Phase IIa, randomized, double-blind study of remimazolam (CNS 7056) versus midazolam for sedation in upper gastrointestinal endoscopy". Anesthesia & Analgesia. 120 (4): 771–80. doi:10.1213/ANE.0000000000000548. PMID 25502841. S2CID 20941788.
  16. ↑ Stafford, Jeffrey A.; Pacofsky, Gregory J.; Cox, Richard F.; Cowan, Jill R.; Dorsey, George F.; Gonzales, Stephen S.; Jung, David K.; Koszalka, George W.; McIntyre, Maggie S.; Tidwell, Jeffrey H.; Wiard, Robert P. (2002-11-04). "Identification and structure-activity studies of novel ultrashort-acting benzodiazepine receptor agonists". Bioorganic & Medicinal Chemistry Letters. 12 (21): 3215–3218. doi:10.1016/s0960-894x(02)00512-7. ISSN 0960-894X. PMID 12372537. Archived from the original on 2022-10-24. Retrieved 2022-04-23.
  17. ↑ Pacofsky, Gregory J.; Stafford, Jeffrey A.; Cox, Richard F.; Cowan, Jill R.; Dorsey, George F.; Gonzales, Stephen S.; Kaldor, Istvan; Koszalka, George W.; Lovell, George G.; McIntyre, Maggie S.; Tidwell, Jeffrey H. (2002-11-04). "Relating the structure, activity, and physical properties of ultrashort-acting benzodiazepine receptor agonists". Bioorganic & Medicinal Chemistry Letters. 12 (21): 3219–3222. doi:10.1016/s0960-894x(02)00513-9. ISSN 0960-894X. PMID 12372538. Archived from the original on 2022-10-24. Retrieved 2022-04-23.
  18. ↑ US 7473689, Feldman, Paul L.; David Kendall Jung & Istvan Kaldor et al., "Short-acting benzodiazepines", published 2009-01-06, assigned to CeNes Ltd. 
Identifiers:
  • "Remimazolam". Drug Information Portal. United States National Library of Medicine. Archived from the original on 2020-07-03. Retrieved 2022-04-23.
  • Clinical trial number NCT02290873 for "A Phase III Study of the Efficacy and Safety of Remimazolam Compared to Placebo and Midazolam in Colonoscopy Patients" at ClinicalTrials.gov
  • Clinical trial number NCT02296892 for "A Phase III Study of Remimazolam in Patients Undergoing Bronchoscopy" at ClinicalTrials.gov
  • Clinical trial number NCT02532647 for "Safety and Efficacy of Remimazolam in ASA III and IV Patients Undergoing Colonoscopy" at ClinicalTrials.gov
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