imported>BoletusLuridus: otic insertion? first time i hear of that route of administration, sounds amusing but there's no citation or plausiblity, so...

2025-10-04T17:26:55Z

otic insertion? first time i hear of that route of administration, sounds amusing but there's no citation or plausiblity, so...

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{{Short description|GABA receptor antagonist drug and benzodiazepine antidote}}
{{Use dmy dates|date=April 2025}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Drugbox
| Watchedfields = changed
| verifiedrevid = 461101379
| image = Flumazenil.svg
| image_class = skin-invert-image
| width = 222
| alt =
| image2 = Flumazenil ball-and-stick model.png
| alt2 =


| tradename = Anexate, others
| Drugs.com = {{drugs.com|monograph|flumazenil}}
| DailyMedID = Flumazenil
| pregnancy_AU = B3
| routes_of_administration = [[Intranasal administration|Intranasal]], [[intravenous administration|intravenous]]
| ATC_prefix = V03
| ATC_suffix = AB25
| ATC_supplemental =

| legal_AU = S4
| legal_BR = C1
| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=16 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>
| legal_CA = Rx-only
| legal_UK = POM
| legal_US = Rx-only
| legal_status = Rx-only


| bioavailability =
| protein_bound =
| metabolism = Liver
| elimination_half-life = 7–15 min (initial) 20–30 min (brain) 40–80 min (terminal)
| excretion = Urine 90–95% Feces 5–10%


| IUPHAR_ligand = 4192
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 78755-81-4
| PubChem = 3373
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01205
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3256
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 40P7XK9392
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00697
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 5103
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 407


| IUPAC_name = Ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4''H''-benzo[''f'']imidazo[1,5-''a''][1,4]diazepine-3-carboxylate
| C = 15
| H = 14
| F = 1
| N = 3
| O = 3
| smiles = Fc(c1)ccc-2c1C(=O)N(C)Cc3n2cnc3C(=O)OCC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = OFBIFZUFASYYRE-UHFFFAOYSA-N
| synonyms = ethyl 8-fluoro- 5,6-dihydro- 5-methyl- 6-oxo- 4''H''- imidazo [1,5-''a''] [1,4] benzodiazepine- 3-carboxylate, RO 15-1788
}}

[[Image:Flumazenil1.JPG|thumb|A vial of flumazenil solution for injection]]

'''Flumazenil''', also known as '''flumazepil''',<ref>{{cite journal | vauthors = Hunkeler W, Möhler H, Pieri L, Polc P, Bonetti EP, Cumin R, Schaffner R, Haefely W | display-authors = 6 | title = Selective antagonists of benzodiazepines | journal = Nature | volume = 290 | issue = 5806 | pages = 514–516 | date = April 1981 | pmid = 6261143 | doi = 10.1038/290514a0 | s2cid = 4340263 | bibcode = 1981Natur.290..514H }}</ref> is a selective [[GABAA receptor|GABAA]] [[receptor antagonist]]<ref>{{cite journal | vauthors = Whitwam JG, Amrein R | title = Pharmacology of flumazenil | journal = Acta Anaesthesiologica Scandinavica. Supplementum | volume = 108 | pages = 3–14 | date = 1 January 1995 | pmid = 8693922 | doi = 10.1111/j.1399-6576.1995.tb04374.x | s2cid = 24494744 }}</ref> administered via injection, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines (particularly in cases of overdose), through [[competitive inhibition]].

It was first characterized in 1981,<ref>{{cite journal | vauthors = Whitwam JG | title = Flumazenil: a benzodiazepine antagonist | journal = BMJ | volume = 297 | issue = 6655 | pages = 999–1000 | date = October 1988 | pmid = 2903780 | pmc = 1834756 | doi = 10.1136/bmj.297.6655.999 }}</ref> and was first marketed in 1987 by [[Hoffmann-La Roche]] under the trade name '''Anexate'''. However, it did not receive FDA approval until December 1991. The developer lost its exclusive patent rights in 2008 and generic formulations are available. [[Intravenous therapy|Intravenous]] flumazenil is primarily used to treat [[benzodiazepine overdoses]] and to help reverse anesthesia. Administration of flumazenil by [[sublingual administration|sublingual]] lozenge and topical cream has also been tested.<ref name="ref-orig-13">{{cite journal | vauthors = Rye DB, Bliwise DL, Parker K, Trotti LM, Saini P, Fairley J, Freeman A, Garcia PS, Owens MJ, Ritchie JC, Jenkins A | display-authors = 6 | title = Modulation of vigilance in the primary hypersomnias by endogenous enhancement of GABAA receptors | journal = Science Translational Medicine | volume = 4 | issue = 161 | pages = 161ra151 | date = November 2012 | pmid = 23175709 | doi = 10.1126/scitranslmed.3004685 | s2cid = 44236050 }}</ref><ref>{{ClinicalTrialsGov|NCT01183312|Flumazenil for the Treatment of Primary Hypersomnia}}</ref>

==Medical uses==
Flumazenil benefits people who become excessively drowsy after use of [[benzodiazepine]]s for either [[medical diagnosis|diagnostic]] or [[therapeutic]] procedures.<ref name=gold2002>{{cite book | vauthors = Goldfrank LR |title=Goldfrank's toxicologic emergencies |publisher=McGraw-Hill Medical Publ. Division |location=New York |year=2002 |isbn=978-0-07-136001-2 |url=https://books.google.com/books?id=HVYyRsuUEc0C&q=flumazenil+not+to+be+used+in+overdose&pg=PA948}}</ref>

Flumazenil has been used as an [[antidote]] in the treatment of benzodiazepine overdoses.<ref name=gold2002/> It reverses the effects of benzodiazepines by [[competitive inhibitor|competitive inhibition]] at the benzodiazepine (BZ) recognition site on the [[GABA]]/benzodiazepine receptor complex.<ref name=gold2002/>

Flumazenil has been effectively used to treat overdoses of non-benzodiazepine hypnotics, such as [[zolpidem]], [[zaleplon]] and [[zopiclone]] (also known as the "Z-drugs").<ref>{{cite book | vauthors = Nelson LH, Flomenbaum N, Goldfrank LR, Hoffman RL, Howland MD, Lewin NA |title=Goldfrank's toxicologic emergencies |publisher=McGraw-Hill, Medical Pub. Division |location=New York |year=2006 |isbn=978-0-07-147914-1 }}</ref>

It may also be effective in reducing [[excessive daytime sleepiness]] while improving [[Vigilance (psychology)|vigilance]] in primary [[hypersomnias]], such as [[idiopathic hypersomnia]].<ref name="ref-orig-13"/>

Flumazenil has also been used in [[hepatic encephalopathy]]. It may have beneficial short‐term effects in people with [[cirrhosis]], but there is no evidence for long-term benefits.<ref>{{cite journal | vauthors = Goh ET, Andersen ML, Morgan MY, Gluud LL | title = Flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | issue = 8 | article-number = CD002798 | date = August 2017 | pmid = 28796283 | pmc = 6483298 | doi = 10.1002/14651858.CD002798.pub4 }}</ref>

The onset of action is rapid, and effects are usually seen within one to two minutes. The peak effect is seen at six to ten minutes. The recommended dose for adults is 200 μg every 1–2 minutes until the effect is seen, up to a maximum of 3 mg per hour. It is available as a clear, colourless solution for [[intravenous injection]], containing 500 μg in 5 mL.{{citation needed|date=December 2022}} Additional doses may be needed within 20 to 30 minutes if evidence of oversedation reappears.<ref name=Mihic2023>{{cite book | vauthors = Mihic S, Mayfield J | date = 2023 | chapter = Hypnotics and sedatives. | veditors = Brunton LL, Knollmann BC | title = Goodman & Gilman's: The Pharmacological Basis of Therapeutics | edition = 14th | publisher = McGraw Hill | chapter-url = https://accessanesthesiology.mhmedical.com/content.aspx?bookid=3191&sectionid=269719266 | isbn = 978-1-264-25807-9 }}</ref>

It is not recommended for routine use in those with a decreased [[level of consciousness]].<ref>{{cite book | vauthors = Wood LD, Hall JB, Schmidt GD |title=Principles of critical care |publisher=McGraw-Hill Professional |year=2005 |isbn=978-0-07-141640-5 |url=https://books.google.com/books?id=Ss7gzGwk78gC&q=flumazenil+not+recommended+in+overdose&pg=RA11-PA1505 }}</ref>

In terms of drug enforcement initiatives, diversion control programs and required post-marketing surveillance of adverse events, orders for flumazenil may trigger a prescription audit to the search for benzodiazepine misuse and for clinically significant adverse reactions related to their use.<ref>{{cite journal | vauthors = Kawano DF, Ueta J, Sankarankutty AK, Pereira LR, de Freitas O | title = Midazolam-related drug interactions: detection of risk situations to the patient safety in a brazilian teaching hospital | journal = Journal of Patient Safety | volume = 5 | issue = 2 | pages = 69–74 | date = June 2009 | pmid = 19920444 | doi = 10.1097/PTS.0b013e3181a5dafa | s2cid = 12973546 }}</ref>

===PET radioligand===
Radiolabeled with the radioactive isotope [[carbon-11]], flumazenil may be used as a [[radioligand]] in [[neuroimaging]] with [[positron emission tomography]] to visualize the distribution of [[GABAA receptor|GABAA receptors]] in the human brain.<ref>{{cite journal | vauthors = Hammers A, Koepp MJ, Richardson MP, Hurlemann R, Brooks DJ, Duncan JS | title = Grey and white matter flumazenil binding in neocortical epilepsy with normal MRI. A PET study of 44 patients | journal = Brain | volume = 126 | issue = Pt 6 | pages = 1300–1318 | date = June 2003 | pmid = 12764053 | doi = 10.1093/brain/awg138 | name-list-style = amp | doi-access = free }}</ref>

===Treatment for benzodiazepine dependence & tolerance===
Epileptic patients who have become tolerant to the anti-seizure effects of the benzodiazepine clonazepam became seizure-free for several days after treatment with 1.5 mg of flumazenil.<ref name="Savic1991">{{cite journal | vauthors = Savic I, Widén L, Stone-Elander S | title = Feasibility of reversing benzodiazepine tolerance with flumazenil | journal = Lancet | volume = 337 | issue = 8734 | pages = 133–137 | date = January 1991 | pmid = 1670787 | doi = 10.1016/0140-6736(91)90799-U | s2cid = 41180892 }}</ref> Similarly, patients who were dependent on high doses of benzodiazepines (median dosage 333 mg diazepam-equivalent) were able to be stabilised on a low dose of clonazepam after 7–8 days of treatment with flumazenil.<ref name="QuaglioPattaro2012">{{cite journal | vauthors = Quaglio G, Pattaro C, Gerra G, Mathewson S, Verbanck P, Des Jarlais DC, Lugoboni F | title = High dose benzodiazepine dependence: description of 29 patients treated with flumazenil infusion and stabilised with clonazepam | journal = Psychiatry Research | volume = 198 | issue = 3 | pages = 457–462 | date = August 2012 | pmid = 22424905 | doi = 10.1016/j.psychres.2012.02.008 | s2cid = 28979824 }}</ref>

Flumazenil has been tested against placebo in benzodiazepine-dependent subjects. Results showed that typical benzodiazepine withdrawal effects were reversed with few to no symptoms.<ref>{{cite journal | vauthors = Gerra G, Giucasto G, Zaimovic A, Fertonani G, Chittolini B, Avanzini P, Caccavari R, Delsignore R | display-authors = 6 | title = Intravenous flumazenil following prolonged exposure to lormetazepam in humans: lack of precipitated withdrawal | journal = International Clinical Psychopharmacology | volume = 11 | issue = 2 | pages = 81–88 | date = June 1996 | pmid = 8803645 | doi = 10.1097/00004850-199611020-00002 | name-list-style = amp }}</ref> Flumazenil was also shown to produce significantly fewer withdrawal symptoms than saline in a randomized, placebo-controlled study with benzodiazepine-dependent subjects. Additionally, relapse rates were much lower during subsequent follow-up.<ref name="GerraZaimovic2002">{{cite journal | vauthors = Gerra G, Zaimovic A, Giusti F, Moi G, Brewer C | title = Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo-controlled study | journal = Addiction Biology | volume = 7 | issue = 4 | pages = 385–395 | date = October 2002 | pmid = 14578014 | doi = 10.1080/1355621021000005973 | s2cid = 21255719 }}</ref>

[[In vitro]] studies of tissue cultured cell lines have shown that chronic treatment with flumazenil enhanced the benzodiazepine binding site where such receptors have become more numerous and uncoupling/down-regulation of GABAA has been reversed.<ref>{{cite journal | vauthors = Pericić D, Lazić J, Strac DS | title = Chronic treatment with flumazenil enhances binding sites for convulsants at recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptors | journal = Biomedicine & Pharmacotherapy | volume = 59 | issue = 7 | pages = 408–414 | date = August 2005 | pmid = 16084060 | doi = 10.1016/j.biopha.2005.02.003 | name-list-style = amp }}</ref><ref>{{cite journal | vauthors = Pericić D, Jazvinsćak Jembrek M, Svob Strac D, Lazić J, Spoljarić IR | title = Enhancement of benzodiazepine binding sites following chronic treatment with flumazenil | journal = European Journal of Pharmacology | volume = 507 | issue = 1–3 | pages = 7–13 | date = January 2005 | pmid = 15659288 | doi = 10.1016/j.ejphar.2004.10.057 | name-list-style = amp }}</ref><ref>{{cite journal | vauthors = Pericić D, Lazić J, Jembrek MJ, Strac DS, Rajcan I | title = Chronic exposure of cells expressing recombinant GABAA receptors to benzodiazepine antagonist flumazenil enhances the maximum number of benzodiazepine binding sites | journal = Life Sciences | volume = 76 | issue = 3 | pages = 303–317 | date = December 2004 | pmid = 15531382 | doi = 10.1016/j.lfs.2004.07.013 | name-list-style = amp }}</ref> After long-term exposure to benzodiazepines, GABAA receptors become down-regulated and uncoupled. Growth of new receptors and recoupling after prolonged flumazenil exposure has also been observed. It is thought this may be due to increased synthesis of receptor proteins.<ref>{{cite journal | vauthors = Jazvinsćak Jembrek M, Svob Strac D, Vlainić J, Pericić D | title = The role of transcriptional and translational mechanisms in flumazenil-induced up-regulation of recombinant GABA(A) receptors | journal = Neuroscience Research | volume = 61 | issue = 3 | pages = 234–241 | date = July 2008 | pmid = 18453026 | doi = 10.1016/j.neures.2008.03.005 | name-list-style = amp | s2cid = 9033302 }}</ref>

Flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks.<ref>{{cite journal | vauthors = Saxon L, Borg S, Hiltunen AJ | title = Reduction of aggression during benzodiazepine withdrawal: effects of flumazenil | journal = Pharmacology, Biochemistry, and Behavior | volume = 96 | issue = 2 | pages = 148–151 | date = August 2010 | pmid = 20451546 | doi = 10.1016/j.pbb.2010.04.023 | name-list-style = amp | s2cid = 41351863 }}</ref> This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.

Low-dose, slow [[subcutaneous injection|subcutaneous]] flumazenil administration is a safe procedure for patients withdrawing from long-term, high-dose benzodiazepine dependency.<ref>{{cite journal | vauthors = Faccini M, Leone R, Opri S, Casari R, Resentera C, Morbioli L, Conforti A, Lugoboni F | display-authors = 6 | title = Slow subcutaneous infusion of flumazenil for the treatment of long-term, high-dose benzodiazepine users: a review of 214 cases | journal = Journal of Psychopharmacology | volume = 30 | issue = 10 | pages = 1047–1053 | date = October 2016 | pmid = 27166362 | doi = 10.1177/0269881116647505 | s2cid = 27167585 }}</ref> It has a low risk of seizures even amongst those who have experienced convulsions when previously attempting benzodiazepine withdrawal.<ref>{{cite journal | vauthors = Tamburin S, Faccini M, Casari R, Federico A, Morbioli L, Franchini E, Bongiovanni LG, Lugoboni F | display-authors = 6 | title = Low risk of seizures with slow flumazenil infusion and routine anticonvulsant prophylaxis for high-dose benzodiazepine dependence | journal = Journal of Psychopharmacology | volume = 31 | issue = 10 | pages = 1369–1373 | date = October 2017 | pmid = 28613124 | doi = 10.1177/0269881117714050 | s2cid = 42432213 }}</ref>

In Italy, the gold standard for treatment of high-dose benzodiazepine dependency is 8–10 days of low-dose, slowly infused flumazenil.<ref name="LugoboniFaccini2011">{{cite journal | vauthors = Lugoboni F, Faccini M, Quaglio G, Casari R, Albiero A, Pajusco B | title = Agonist substitution for high-dose benzodiazepine-dependent patients: let us not forget the importance of flumazenil | journal = Addiction | volume = 106 | issue = 4 | page = 853 | date = April 2011 | pmid = 21320225 | doi = 10.1111/j.1360-0443.2010.03327.x | doi-access = free }}</ref> One addiction treatment centre in Italy has used flumazenil to treat over 300 patients who were dependent on high doses of benzodiazepines (up to 70 times higher than conventionally prescribed) with physicians being among the clinic's most common patients.<ref name="LugoboniLeone2012">{{cite journal | vauthors = Lugoboni F, Leone R | title = What is stopping us from using flumazenil? | journal = Addiction | volume = 107 | issue = 7 | page = 1359 | date = July 2012 | pmid = 22509854 | doi = 10.1111/j.1360-0443.2012.03851.x | doi-access = free }}</ref>

==Pharmacology==
[[File:6X3U GABAAR Flumazenil.png|thumb|Flumazenil bound at the alpha-gamma interface of an α1β2γ2 GABAA receptor. H-atoms hidden.]]

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 [[GABAA receptor|GABA/benzodiazepine receptor complex]].<ref>{{cite journal | vauthors = Hood SD, Norman A, Hince DA, Melichar JK, Hulse GK | title = Benzodiazepine dependence and its treatment with low dose flumazenil | journal = British Journal of Clinical Pharmacology | volume = 77 | issue = 2 | pages = 285–294 | date = February 2014 | pmid = 23126253 | pmc = 4014019 | doi = 10.1111/bcp.12023 }}</ref> It also exhibits weak partial agonism of GABAA receptor complexes that contain [[GABRA6|α6-type monomers]]; the clinical relevance of this is unknown.<ref>{{cite journal | vauthors = Hadingham KL, Garrett EM, Wafford KA, Bain C, Heavens RP, Sirinathsinghji DJ, Whiting PJ | title = Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors | journal = Molecular Pharmacology | volume = 49 | issue = 2 | pages = 253–259 | date = February 1996 | doi = 10.1016/S0026-895X(25)08706-1 | pmid = 8632757 }}</ref>

Flumazenil does not antagonize all of the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, and most anesthetics) and does not reverse the effects of opioids. It will however antagonize the action of non-benzodiazepine [[z-drug]]s, such as [[zolpidem]] and [[zopiclone]], because they act via the [[GABAA receptor#Target for benzodiazepines|benzodiazepine site]] of the GABA receptor<ref name="Gunja 155–162">{{cite journal | vauthors = Gunja N | title = The clinical and forensic toxicology of Z-drugs | journal = Journal of Medical Toxicology | volume = 9 | issue = 2 | pages = 155–162 | date = June 2013 | pmid = 23404347 | pmc = 3657020 | doi = 10.1007/s13181-013-0292-0 }}</ref> - it has been used to successfully treat z-drug overdose.<ref name="Gunja 155–162"/><ref>{{cite journal | vauthors = Thornton SL, Negus E, Carstairs SD | title = Pediatric zolpidem ingestion demonstrating zero-order kinetics treated with flumazenil | journal = Pediatric Emergency Care | volume = 29 | issue = 11 | pages = 1204–1206 | date = November 2013 | pmid = 24196090 | doi = 10.1097/PEC.0b013e3182aa139c | s2cid = 34655918 }}</ref><ref>{{cite journal | vauthors = Lheureux P, Debailleul G, De Witte O, Askenasi R | title = Zolpidem intoxication mimicking narcotic overdose: response to flumazenil | journal = Human & Experimental Toxicology | volume = 9 | issue = 2 | pages = 105–107 | date = March 1990 | pmid = 2111156 | doi = 10.1177/096032719000900209 | bibcode = 1990HETox...9..105L | s2cid = 34525063 }}</ref>

===Pharmacodynamics===
Intravenous flumazenil has been shown to antagonize [[sedation]], impairment of recall, psychomotor impairment and ventilatory depression produced by benzodiazepines in healthy human volunteers.

The duration and degree of reversal of [[sedative]] benzodiazepine effects are related to the dose and plasma concentrations of flumazenil.

== Availability ==
Flumazenil is sold under a wide variety of brand names worldwide like Anexate, Lanexat, Mazicon, Romazicon.

== References ==
{{Reflist}}

== External links ==
* {{Commons category-inline}}

{{Benzodiazepines}}
{{Antidotes}}
{{GABA receptor modulators}}
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[[Category:Anxiogenics]]
[[Category:Carboxylate esters]]
[[Category:Chemical substances for emergency medicine]]
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[[Category:GABAA receptor negative allosteric modulators]]
[[Category:Drugs developed by Hoffmann-La Roche]]
[[Category:Imidazobenzodiazepines]]
[[Category:Lactams]]
[[Category:Wakefulness-promoting agents]]

Flumazenil - Revision history

imported>BoletusLuridus: otic insertion? first time i hear of that route of administration, sounds amusing but there's no citation or plausiblity, so...