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Revision as of 12:42, 17 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 448330631 of page Flurazepam for the Chem/Drugbox validation project (updated: 'DrugBank').		Latest revision as of 09:17, 5 September 2024 edit JWBE (talk | contribs)Extended confirmed users10,126 edits removed Category:Fluoroarenes; added Category:2-Fluorophenyl compounds using HotCat
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			{{Short description|Hypnotic medication}}
	{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
			{{Infobox drug
	{{Drugbox
	| Watchedfields = changed		| Watchedfields = changed
	| verifiedrevid = 413084575		| verifiedrevid = 461102409
			| drug_name =
	| IUPAC_name = 7-chloro-1--5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one
			| type =
	| image = Flurazepam.svg
			| IUPAC_name = 7-Chloro-1--5-(2-fluorophenyl)-1,3-dihydro-2''H''-1,4-benzodiazepin-2-one
	| image2 = Flurazepam3d.png
			| image = Flurazepam.svg
			| width = 185
	<!--Clinical data-->
			| alt =
	| tradename = Dalmane
			| caption =
	| Drugs.com = {{drugs.com|monograph|flurazepam-hydrochloride}}
			| image2 = Flurazepam3d.png
	| MedlinePlus = a682051
			| width2 = 140
			<!--Clinical data-->| tradename = Dalmane, Dalmadorm, Fluzepam
			| Drugs.com = {{drugs.com|monograph|flurazepam-hydrochloride}}
			| MedlinePlus = a682051
			| licence_EU =
			| licence_US =
			| pregnancy_AU =
	| pregnancy_category = X (Contraindicated in pregnancy)		| pregnancy_category = X (Contraindicated in pregnancy)
			| legal_BR = B1
	| legal_US = Schedule IV
			| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |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=2023-08-03 |access-date=2023-08-16 |publisher=] |language=pt-BR |publication-date=2023-04-04}}</ref>
	| routes_of_administration = Oral
			| legal_CA = Schedule IV
			| legal_DE = Rx-only/Anlage III
			| legal_US = Schedule IV
			| legal_status =
			| addiction_liability = Moderate
			| routes_of_administration = ]
			| class = ]
			<!--Pharmacokinetic data-->| bioavailability = 83%
			| metabolism = ]
			| metabolites = ] (])
			| elimination_half-life = 2.3 hours<br /> ''N''-desalkylflurazepam: 47–100 hours
			| excretion = ]
			<!--Identifiers-->| IUPHAR_ligand = 7188
			| CAS_number_Ref = {{cascite|correct|??}}
			| CAS_number = 17617-23-1
			| ATC_prefix = N05
			| ATC_suffix = CD01
			| ATC_supplemental =
			| PubChem = 3393
			| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
			| DrugBank = DB00690
			| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
			| ChemSpiderID = 3276
			| UNII_Ref = {{fdacite|correct|FDA}}
			| UNII = IHP475989U
			| KEGG_Ref = {{keggcite|correct|kegg}}
			| KEGG = D00329
			| ChEBI = 5128
			| ChEMBL_Ref = {{ebicite|correct|EBI}}
			| ChEMBL = 968
			| PDB_ligand = FL7
			<!--Chemical data-->| C = 21
			| H = 23
			| Cl = 1
			| F = 1
			| N = 3
			| O = 1
			| smiles = FC1=CC=CC=C1C2=NCC(N(CCN(CC)CC)C3=C2C=C(C=C3)Cl)=O
			| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
			| StdInChI = 1S/C21H23ClFN3O/c1-3-25(4-2)11-12-26-19-10-9-15(22)13-17(19)21(24-14-20(26)27)16-7-5-6-8-18(16)23/h5-10,13H,3-4,11-12,14H2,1-2H3
			| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
			| StdInChIKey = SAADBVWGJQAEFS-UHFFFAOYSA-N
			| melting_point = 79.5
			}}
			'''Flurazepam'''<ref>{{cite patent | country = BE | number = 629005}}</ref> (marketed under the brand names '''Dalmane''' and '''Dalmadorm''') is a drug which is a ] derivative. It possesses ], ], ], ] and ] properties. It produces a metabolite with a long ], which may stay in the bloodstream for days.<ref name="dailymed.nlm.nih.gov">{{Cite web|url=https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=8226|title=FLURAZEPAM HCl CAPSULES, USP|website=dailymed.nlm.nih.gov}}</ref>
	<!--Pharmacokinetic data-->
			<!-- History, society and culture -->
	| bioavailability = 83%
			Flurazepam was patented in 1968 and came into medical use the same year.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=538 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA538 |language=en}}</ref> Flurazepam, developed by Roche Pharmaceuticals, was one of the first benzodiazepine ] to be marketed.<ref>{{cite book| vauthors = Shorter E |title=A Historical Dictionary of Psychiatry |date=2005 |publisher=Oxford University Press |isbn=978-0-19-029201-0|chapter-url=https://books.google.com/books?id=juAJCAAAQBAJ&pg=PT66 |chapter=B}}</ref>
	| metabolism = ]
	| elimination_half-life = 40–250 hours
	| excretion = ]
			== Medical uses ==
	<!--Identifiers-->
			]]]
	| CASNo_Ref = {{cascite|correct|CAS}}
	| CAS_number = 17617-23-1
	| ATC_prefix = N05
	| ATC_suffix = CD01
	| ATC_supplemental =
	| PubChem = 3393
	| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
	| DrugBank = DB00690
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 3276
	| UNII_Ref = {{fdacite|correct|FDA}}
	| UNII = IHP475989U
	| KEGG_Ref = {{keggcite|correct|kegg}}
	| KEGG = D00329
	| ChEMBL_Ref = {{ebicite|correct|EBI}}
	| ChEMBL = 968
			Flurazepam is officially indicated for mild to moderate insomnia and as such it is used for short-term treatment of patients with mild to moderate ] such as difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Flurazepam is a long-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep, though benzodiazepines with intermediate half-lives such as ], ], and ] are also indicated for patients with difficulty maintaining sleep.
	<!--Chemical data-->
	| C=21 | H=23 | Cl=1 | F=1 | N=3 | O=1
			Flurazepam was temporarily unavailable in the United States when its sole producer, Mylan Pharmaceuticals, discontinued making it in January 2019.{{citation needed|date=October 2019}} In October 2019, the FDA informed pharmacies that they could expect to be resupplied by manufacturers in early to mid December 2019. As of this date,{{when|date=May 2023}} flurazepam is now again available in the United States.
	| molecular_weight = 387.88 g/mol
	| smiles = Fc3ccccc3C/2=N/CC(=O)N(c1c\2cc(Cl)cc1)CCN(CC)CC
			== Side effects ==
	| InChI = 1/C21H23ClFN3O/c1-3-25(4-2)11-12-26-19-10-9-15(22)13-17(19)21(24-14-20(26)27)16-7-5-6-8-18(16)23/h5-10,13H,3-4,11-12,14H2,1-2H3
			The most common adverse effects are dizziness, drowsiness, light-headedness, and ]. Flurazepam has abuse potential and should never be used with ]s or any other substance that can cause drowsiness. Addictive and possibly fatal results may occur. Flurazepam users should only take this drug strictly as prescribed, and should only be taken directly before the user plans on sleeping a full night. Next day drowsiness is common and may increase during the initial phase of treatment as accumulation occurs until steady-state plasma levels are attained.
	| InChIKey = SAADBVWGJQAEFS-UHFFFAOYAO
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
			A 2009 meta-analysis found a 44% higher rate of mild ]s, such as ] or ], in people taking hypnotic drugs compared to those taking a placebo.<ref>{{cite journal | vauthors = Joya FL, Kripke DF, Loving RT, Dawson A, Kline LE | title = Meta-analyses of hypnotics and infections: eszopiclone, ramelteon, zaleplon, and zolpidem | journal = Journal of Clinical Sleep Medicine | volume = 5 | issue = 4 | pages = 377–383 | date = August 2009 | pmid = 19968019 | pmc = 2725260 | doi = 10.5664/jcsm.27552 }}</ref>
	| StdInChI = 1S/C21H23ClFN3O/c1-3-25(4-2)11-12-26-19-10-9-15(22)13-17(19)21(24-14-20(26)27)16-7-5-6-8-18(16)23/h5-10,13H,3-4,11-12,14H2,1-2H3
	| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
			In September 2020, the U.S. ] (FDA) required the ] be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.<ref>{{cite web | title=FDA expands Boxed Warning to improve safe use of benzodiazepine drug | website=U.S. ] (FDA) | date=23 September 2020 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class | access-date=23 September 2020}} {{PD-notice}}</ref>
	| StdInChIKey = SAADBVWGJQAEFS-UHFFFAOYSA-N
	| melting_point = 79.5
			=== Tolerance, dependence and withdrawal ===
	}}
			{{Main|Benzodiazepine withdrawal syndrome}}
			A review paper found that long-term use of flurazepam is associated with ], ], ] and central nervous system (CNS) related adverse effects. Flurazepam is best used for a short time period and at the lowest possible dose to avoid complications associated with long-term use. Non-pharmacological treatment options however, were found to have sustained improvements in sleep quality.<ref>{{cite journal | vauthors = Kirkwood CK | title = Management of insomnia | journal = Journal of the American Pharmaceutical Association | volume = 39 | issue = 5 | pages = 688–96; quiz 713–4 | year = 1999 | pmid = 10533351 | doi = 10.1016/s1086-5802(15)30354-5 }}</ref> Flurazepam and other benzodiazepines such as ], and ] lost some of their effect after seven days administration in ] patients.<ref>{{cite journal | vauthors = Viukari M, Linnoila M, Aalto U | title = Efficacy and side effects of flurazepam, fosazepam, and nitrazepam as sleeping aids in psychogeriatric patients | journal = Acta Psychiatrica Scandinavica | volume = 57 | issue = 1 | pages = 27–35 | date = January 1978 | pmid = 24980 | doi = 10.1111/j.1600-0447.1978.tb06871.x | s2cid = 23137060 }}</ref> Flurazepam shares cross tolerance with barbiturates and ] can easily be substituted by flurazepam in those who are habituated to barbiturate sedative hypnotics.<ref>{{cite journal | vauthors = Rooke KC | title = The use of flurazepam (dalmane) as a substitute for barbiturates and methaqualone/diphenhydramine (mandrax) in general practice | journal = The Journal of International Medical Research | volume = 4 | issue = 5 | pages = 355–359 | year = 1976 | pmid = 18375 | doi = 10.1177/030006057600400510 | s2cid = 23780461 }}</ref>
			After discontinuation of flurazepam a ] or ] may occur about four days after discontinuation of medication.<ref>{{cite journal | vauthors = Hindmarch I | title = A repeated dose comparison of three benzodiazepine derivative (nitrazepam, flurazepam and flunitrazepam) on subjective appraisals of sleep and measures of psychomotor performance the morning following night-time medication | journal = Acta Psychiatrica Scandinavica | volume = 56 | issue = 5 | pages = 373–381 | date = November 1977 | pmid = 22990 | doi = 10.1111/j.1600-0447.1977.tb06678.x | s2cid = 38591190 }}</ref>
			== Contraindications and special caution ==
			Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol- or drug-dependent individuals and individuals with ] ].<ref>{{cite journal | vauthors = Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, Vennat B, Llorca PM, Eschalier A | display-authors = 6 | title = Benzodiazepine dependence: focus on withdrawal syndrome | journal = Annales Pharmaceutiques Françaises | volume = 67 | issue = 6 | pages = 408–413 | date = November 2009 | pmid = 19900604 | doi = 10.1016/j.pharma.2009.07.001 }}</ref>
			=== Elderly ===
			Flurazepam, similar to other benzodiazepines and ] ] drugs causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments.<ref name="Mets-2010">{{cite journal | vauthors = Mets MA, Volkerts ER, Olivier B, Verster JC | title = Effect of hypnotic drugs on body balance and standing steadiness | journal = Sleep Medicine Reviews | volume = 14 | issue = 4 | pages = 259–267 | date = August 2010 | pmid = 20171127 | doi = 10.1016/j.smrv.2009.10.008 }}</ref> An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines including flurazepam, the ] sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy in elderly persons. Tolerability in elderly patients, however, is improved marginally in that benzodiazepines have moderately higher risks of falls, memory problems, and disinhibition ("paradoxical agitation") when compared to non-benzodiazepine sedatives. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Chronic use of sedative-hypnotic drugs for the management of insomnia does not have an evidence base and has been discouraged due to concerns including potential adverse drug effects as cognitive impairment (]), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of sedative hypnotics has been determined to be no better than placebo after 3 months of therapy and worse than placebo after 6 months of therapy.<ref>NEJM, 1983, 1994, et seq. {{full citation needed|date=October 2019}}</ref><ref>{{cite journal | vauthors = Bain KT | title = Management of chronic insomnia in elderly persons | journal = The American Journal of Geriatric Pharmacotherapy | volume = 4 | issue = 2 | pages = 168–192 | date = June 2006 | pmid = 16860264 | doi = 10.1016/j.amjopharm.2006.06.006 }}</ref>
			== Pharmacology ==
			Flurazepam is a "classical" benzodiazepine; some other classical benzodiazepines include ], ], ], ], ], ], and ].<ref>{{cite journal | vauthors = Braestrup C, Squires RF | title = Pharmacological characterization of benzodiazepine receptors in the brain | journal = European Journal of Pharmacology | volume = 48 | issue = 3 | pages = 263–270 | date = April 1978 | pmid = 639854 | doi = 10.1016/0014-2999(78)90085-7 }}</ref> Flurazepam generates an ], ], with a very long ].<ref name="dailymed.nlm.nih.gov" /> Flurazepam could be therefore unsuitable as a sleeping medication for some individuals due to next-day sedation; however, this same effect may also provide next-day anxiety relief. Residual 'hangover' effects after nighttime administration of flurazepam, such as sleepiness, impaired psychomotor and ] functions, may persist into the next day, which may impair the ability of users to drive safely and increase risks of falls and ].<ref>{{cite journal | vauthors = Vermeeren A | title = Residual effects of hypnotics: epidemiology and clinical implications | journal = CNS Drugs | volume = 18 | issue = 5 | pages = 297–328 | year = 2004 | pmid = 15089115 | doi = 10.2165/00023210-200418050-00003 | s2cid = 25592318 }}</ref>
			Flurazepam is ], is metabolized hepatically via oxidative pathways. The main pharmacological effect of flurazepam is to increase the effect of GABA at the GABA<sub>A</sub> receptor via binding to the benzodiazepine site on the GABA<sub>A</sub> receptor causing an increase influx of chloride ions into the GABA<sub>A</sub> neuron.<ref>{{cite journal | vauthors = Oelschläger H | title = | journal = Schweizerische Rundschau für Medizin Praxis | volume = 78 | issue = 27–28 | pages = 766–772 | date = July 1989 | pmid = 2570451 }}</ref><ref>{{cite journal | vauthors = Lehoullier PF, Ticku MK | title = Benzodiazepine and beta-carboline modulation of GABA-stimulated 36Cl-influx in cultured spinal cord neurons | journal = European Journal of Pharmacology | volume = 135 | issue = 2 | pages = 235–238 | date = March 1987 | pmid = 3034628 | doi = 10.1016/0014-2999(87)90617-0 }}</ref>
			Flurazepam is contraindicated in pregnancy. It is recommended to withdraw flurazepam during breast feeding, as flurazepam is excreted in ].<ref>{{cite journal | vauthors = Olive G, Dreux C | title = | journal = Archives Françaises de Pédiatrie | volume = 34 | issue = 1 | pages = 74–89 | date = January 1977 | pmid = 851373 }}</ref>
			== Misuse ==
			{{See also|Benzodiazepine drug misuse}}
			Flurazepam is a drug with potential for misuse. Two types of drug misuse can occur, either recreational misuse where the drug is taken to achieve a high, or when the drug is continued long term against medical advice.<ref>{{cite journal | vauthors = Griffiths RR, Johnson MW | title = Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds | journal = The Journal of Clinical Psychiatry | volume = 66 | issue = Suppl 9 | pages = 31–41 | year = 2005 | pmid = 16336040 }}</ref>
			=== Legal status ===
			Flurazepam is a Schedule IV drug under the ].<ref>{{cite web|url=https://www.incb.org/incb/en/psychotropic-substances/green-lists.html|title=green-lists|work=incb.org|access-date=2015-12-03|archive-url=https://web.archive.org/web/20151208165257/https://www.incb.org/incb/en/psychotropic-substances/green-lists.html|archive-date=2015-12-08|url-status=dead}}</ref>
			== See also ==
			* ]
			== References ==
			{{Reflist|2}}
			== External links ==
			*
			*
			{{Hypnotics and sedatives}}
			{{Benzodiazepines}}
			{{GABAAR PAMs}}
			{{Glycinergics}}
			]
			]
			]
			]
			]
			]
			]
			]
			]
			]