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Remimazolam

Remimazolam
Clinical data
Trade namesByfavo
Other namesCNS-7056[1]
AHFS/Drugs.comMonograph
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life45 - 70 minutes
Identifiers
  • methyl 3-[(4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H19BrN4O2
Molar mass439.313 g·mol−1
3D model (JSmol)
  • COC(=O)CC[C@@H]1N=C(c2ccccn2)c2cc(Br)ccc2-n2c(C)cnc21
  • 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
 ☒NcheckY (what is this?)  (verify)

Remimazolam, sold under the brand name Byfavo, is a medication for the induction and maintenance of procedural sedation in adults for invasive diagnostic or surgical procedures lasting 30 minutes or less.[2][5][6] It is a benzodiazepine drug, developed by PAION AG in collaboration with several regional licensees as an alternative to the short-acting imidazobenzodiazepine midazolam, for use in the induction of anesthesia and conscious sedation for minor invasive procedures. Remimazolam was found to have both a more rapid onset and a shorter duration than midazolam, and human clinical trials showed a faster recovery time and predictable, consistent pharmacokinetics, suggesting some advantages over existing drugs for these applications.[7][8]

The most common side effects for procedural sedation include low blood pressure, high blood pressure, diastolic hypertension, systolic hypertension, low blood oxygen level, and diastolic hypotension.[5][6]

Remimazolam was approved for medical use in the United States in July 2020,[5][6] and in the European Union in March 2021.[3]

Medical uses

Remimazolam is indicated for the induction and maintenance of procedural sedation in adults (lasting 30 minutes or less in the USA).[5][6][9]

History

Remimazolam was approved for medical use in the United States in July 2020.[5][6]

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.[5] Trials were conducted at 32 sites in the United States.[5]

Trials 1 and 3 were conducted in participants undergoing colonoscopy and Trial 2 was conducted in participants undergoing bronchoscopy procedures.[5]

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).[5] 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.[5] In the third group, all participants received midazolam only[5] Additionally, in all three trials participants received a medication for pain control[5]

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.[5] Data from Trial 3 were used primarily to assess the side effects of remimazolam when multiple dosing is used.[5]

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.[10] The applicant for this medicinal product is PAION Netherlands B.V.[10] Remimazolam (Byfavo) was approved for medical use in the European Union in March 2021.[3]

Research

Phase I[11] and Ib[12] 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.[13]

A Phase IIa trial comparing remimazolam to midazolam for upper endoscopy was published in December 2014, finding a similar safety profile.[14] Remimazolam was originally synthesized in the late 1990s at Glaxo Wellcome in their labs in Research Triangle Park, North Carolina.[15][16][17]

References

  1. ^ Kilpatrick GJ, McIntyre MS, Cox RF, Stafford JA, Pacofsky GJ, Lovell GG, et al. (July 2007). "CNS 7056: a novel ultra-short-acting Benzodiazepine". Anesthesiology. 107 (1): 60–66. doi:10.1097/01.anes.0000267503.85085.c0. PMID 17585216. S2CID 19504961.
  2. ^ a b "Byfavo- remimazolam besylate injection, powder, lyophilized, for solution". DailyMed. 20 July 2020. Retrieved 25 February 2021.
  3. ^ a b c "Byfavo EPAR". European Medicines Agency (EMA). 9 December 2020. Retrieved 20 April 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. ^ "Byfavo Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  5. ^ a b c d e f g h i j k l m n "Drug Trials Snapshots: Byfavo". Food and Drug Administration. 2 July 2020. Retrieved 25 February 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  6. ^ a b c d e "Cosmo Pharmaceuticals Announces US FDA Approval of Byfavo (remimazolam injection) for the Induction and Maintenance of Procedural Sedation". Cosmo Pharmaceuticals NV (Press release). 2 July 2020. Retrieved 25 February 2021.
  7. ^ Rogers WK, McDowell TS (December 2010). "Remimazolam, a short-acting GABA(A) receptor agonist for intravenous sedation and/or anesthesia in day-case surgical and non-surgical procedures". IDrugs. 13 (12): 929–937. PMID 21154153.
  8. ^ Saari TI, Uusi-Oukari M, Ahonen J, Olkkola KT (March 2011). "Enhancement of GABAergic activity: neuropharmacological effects of benzodiazepines and therapeutic use in anesthesiology". Pharmacological Reviews. 63 (1): 243–267. doi:10.1124/pr.110.002717. PMID 21245208. S2CID 930379.
  9. ^ "Byfavo: FDA-Approved Drugs". Food and Drug Administration. Retrieved 25 February 2021.
  10. ^ a b "Byfavo: Pending EC decision". European Medicines Agency. 29 January 2021. Retrieved 25 February 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  11. ^ Antonik LJ, Goldwater DR, Kilpatrick GJ, Tilbrook GS, Borkett KM (August 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): 274–283. doi:10.1213/ANE.0b013e31823f0c28. PMID 22190555. S2CID 21457057.
  12. ^ Worthington MT, Antonik LJ, Goldwater DR, Lees JP, Wilhelm-Ogunbiyi K, Borkett KM, Mitchell MC (November 2013). "A phase Ib, dose-finding study of multiple doses of remimazolam (CNS 7056) in volunteers undergoing colonoscopy". Anesthesia and Analgesia. 117 (5): 1093–1100. doi:10.1213/ANE.0b013e3182a705ae. PMID 24108261. S2CID 24581168.
  13. ^ "Two Scientific Remimazolam Presentations Are Accepted for ASA and ACG Meeting in October 2014". MarketWired. Oct 1, 2014. Retrieved 25 February 2021.
  14. ^ Borkett KM, Riff DS, Schwartz HI, Winkle PJ, Pambianco DJ, Lees JP, Wilhelm-Ogunbiyi K (April 2015). "A Phase IIa, randomized, double-blind study of remimazolam (CNS 7056) versus midazolam for sedation in upper gastrointestinal endoscopy". Anesthesia and Analgesia. 120 (4): 771–780. doi:10.1213/ANE.0000000000000548. PMID 25502841. S2CID 20941788.
  15. ^ Stafford JA, Pacofsky GJ, Cox RF, Cowan JR, Dorsey GF, Gonzales SS, et al. (November 2002). "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. PMID 12372537.
  16. ^ Pacofsky GJ, Stafford JA, Cox RF, Cowan JR, Dorsey GF, Gonzales SS, et al. (November 2002). "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. PMID 12372538.
  17. ^ US 7473689, Feldman PL, Jung DK, Kaldor I, Pacofsky JG, Stafford JA, Tidwell JH, "Short-acting benzodiazepines", published 2009-01-06, assigned to CeNes Ltd. 
  • 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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