Bromazepam: Difference between revisions

{{Short description|Benzodiazepine drug}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 413835339

| IUPAC_name = 7-bromo-5-(pyridin-2-yl)-1''H''-benzo[''e''][1,4]diazepin-2(3''H'')-one

| = Bromazepam.

| width = 222

| image2 = Bromazepam-from-xtal-3D-balls.png

<!--Clinical data-->| tradename = Lexotan, Lexotanil, others

| Drugs.com = {{drugs.com|CONS|bromazepam}}

| legal_BR = B1

| 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=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_CA = Schedule IV

| legal_DE = Rx-only/Anlage III

| legal_UK = Class C

| legal_US = Schedule IV

| addiction_liability = High<ref name="DrugBank">{{cite web |url=https://go.drugbank.com/drugs/DB01558 |title=Bromazepam: Uses, Interactions, Mechanism of Action |accessdate=2024-02-25|website= DrugBank Online}}</ref>

| routes_of_administration = [[Oral administration|By mouth]]

<!--Pharmacokinetic data-->| bioavailability = 84%

| protein_bound = 70%

| metabolism = [[Liver]]: [[P450]]

| metabolites = 3-hydroxybromazepam

| elimination_half-life = 12–20 hours (avg. 17hr)<ref>{{cite web | title = Lexotan (bromazepam) Product Insert | publisher = Roche | date = 23 October 2012 | url = http://e-lactancia.org/media/papers/Bromazepam-DS-2012.pdf}}</ref>

| excretion = [[Urine]] 69%, as metabolites<ref name="DrugBank"/>

<!--Identifiers-->| CAS_number_Ref = {{cascite|correct|??}}

| =

| ATC_prefix = N05

| ATC_suffix = BA08

| PubChem = 2441

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB01558

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 2347

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = X015L14V0O

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D01245

| ChEBI = 31302

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 277062

<!--Chemical data-->| C = 14

| H = 10

| Br = 1

| N = 3

| O = 1

| smiles = C1C(=O)NC2=C(C=C(C=C2)Br)C(=N1)C3=CC=CC=N3

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C14H10BrN3O/c15-9-4-5-11-10(7-9)14(17-8-13(19)18-11)12-3-1-2-6-16-12/h1-7H,8H2,(H,18,19)

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = VMIYHDSEFNYJSL-UHFFFAOYSA-N

<!-- Definition and medical uses -->

'''Bromazepam''', sold under many brand names, is a [[benzodiazepine]]. It is mainly an [[anxiolytic|anti-anxiety]] agent with similar side effects to [[diazepam]]. In addition to being used to treat anxiety or panic states, bromazepam may be used as a premedicant prior to minor surgery. Bromazepam typically comes in doses of 3&nbsp;mg and 6&nbsp;mg tablets.<ref name=B-pam>{{cite web|title=Bromazepam|url=http://www.pbs.gov.au/medicine/item/4150K-4151L|work=Pharmaceutical Benefits Scheme (PBS)|publisher=Australian Government - Department of Health|access-date=23 March 2014}}</ref>

<!-- Society and culture -->

It was patented in 1961 by [[Hoffmann-La Roche|Roche]] and approved for medical use in 1974.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=53X |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA53X |language=en}}</ref>

==Medical uses==

Medical uses include treatment of severe [[anxiety]].<ref>{{Cite web|url=https://www.uptodate.com/contents/bromazepam-drug-information?source=search_result&search=bromazepam&selectedTitle=1~3|title=Content Not Available|website=www.uptodate.com|access-date=2017-09-07}}</ref> Despite certain side effects and the emergence of alternative products (e.g. [[pregabalin]]), benzodiazepine medication remains an effective way of reducing problematic symptoms, and is typically deemed effective by patients<ref>{{cite journal | vauthors = Podiwinsky F, Jellinger K | title = [Bromazepam in the treatment of somatized psychogenic disorders (author's transl)] | language = German | journal = Wiener Klinische Wochenschrift | volume = 91 | issue = 7 | pages = 240–244 | date = March 1979 | pmid = 34934 | trans-title = Bromazepam in the treatment of somatized psychogenic disorders }}</ref><ref>{{cite journal | vauthors = Laxenaire M, Kahn JP, Marchand P | title = [A clinical trial of bromazepam (author's transl)] | language = French | journal = La Nouvelle Presse Médicale | volume = 11 | issue = 22 | pages = 1699–1701 | date = May 1982 | pmid = 6124936 | trans-title = A clinical trial of bromazepam }}</ref> and medical professionals.<ref>{{cite journal | vauthors = Ropert R, Bernes J, Dachary JM | title = [Efficacy and tolerance of alprazolam and bromazepam in flexible doses. Double-blind study in 119 ambulatory anxious patients] | language = French | journal = L'Encéphale | volume = 13 | issue = 2 | pages = 89–95 | date = 1987 | pmid = 2885173 | trans-title = Efficacy and tolerance of alprazolam and bromazepam in flexible doses. Double-blind study in 119 ambulatory anxious patients }}</ref><ref>{{cite journal | vauthors = Hallett C, Dean BC | title = Bromazepam: acute benefit-risk assessment in general practice | journal = Current Medical Research and Opinion | volume = 8 | issue = 10 | pages = 683–688 | date = 11 August 2008 | pmid = 6144455 | doi = 10.1185/03007998409110117 }}</ref><ref>{{cite web | title = Bromazépam | date = 7 September 2016 | url = https://www.has-sante.fr/upload/docs/evamed/CT-15448_LEXOMIL_PIS_RI_avis2_CT15448.pdf | work = Haute Autorité de santé (HAS) | language = French }}</ref>

Similarly to other intermediate-acting [[depressants]], it may be used as hypnotic medication<ref>{{Cite web | url=http://flipper.diff.org/app/items/info/5074 |title = Bromazepam}}</ref> or in order to mitigate withdrawal effects of [[alcohol (drug)|alcohol]] consumption.<ref>{{cite web | title = Bromazépam | work = Répertoire des Spécialités Pharmaceutiques | publisher = ANSM: Agence Nationale de Sécurité du Médicament et des Produits de Santé (French: National Security Agency of Medicines and Health Products) | url = http://agence-prd.ansm.sante.fr/php/ecodex/frames.php?specid=67851467&typedoc=R&ref=R0157296.htm}}</ref><ref>{{cite journal | vauthors = Chweh AY, Lin YB, Swinyard EA | title = Hypnotic action of benzodiazepines: a possible mechanism | journal = Life Sciences | volume = 34 | issue = 18 | pages = 1763–1768 | date = April 1984 | pmid = 6145073 | doi = 10.1016/0024-3205(84)90576-9 }}</ref><ref>{{cite journal | vauthors = Cordingley GJ, Dean BC, Hallett C | title = A multi-centre, double-blind parallel trial of bromazepam ('Lexotan') and lorazepam to compare the acute benefit-risk ratio in the treatment of patients with anxiety | journal = Current Medical Research and Opinion | volume = 9 | issue = 7 | pages = 505–510 | date = 11 August 2008 | pmid = 2863089 | doi = 10.1185/03007998509109625 }}</ref>

==Pharmacology==

[[File:Lexotanil 6 mg.png|thumb|50 Pills of ''Lexotanil'' (containing 6 mg of Bromazepam apiece) as sold by [[Hoffmann-La Roche]] in [[Germany]]]]

Bromazepam is a "classical" benzodiazepine; other classical benzodiazepines include: [[diazepam]], [[clonazepam]], [[oxazepam]], [[lorazepam]], [[nitrazepam]], [[flurazepam]], and [[clorazepate]].<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> Its molecular structure is composed of a [[diazepine]] connected to a [[benzene]] ring and a [[pyridine]] ring, the benzene ring having a single [[nitrogen]] atom that replaces one of the carbon atoms in the ring structure.<ref name="bromazepamstructure">[http://www.eutimia.com/psicofarmacos/ansioliticos/bromazepam.htm Bromazepam] Eutimia.com - Salud Mental. © 1999-2002.</ref> It is a 1,4-benzodiazepine, which means that the nitrogens on the seven-sided diazepine ring are in the 1 and 4 positions.

Bromazepam binds to the [[GABA]] receptor [[GABA A receptor|GABA_A]], causing a conformational change and increasing the inhibitory effects of GABA. It acts as a positive [[Allosteric modulator|modulator]], increasing the receptors' response when activated by GABA itself or an agonist (such as [[Ethanol|alcohol]]). As opposed to [[barbital]], [[Benzodiazepine|BZD]]s are not GABA-receptor activators and rely on increasing the neurotransmitter's natural activity.<ref>{{cite journal | vauthors = Poisbeau P, Gazzo G, Calvel L | title = Anxiolytics targeting GABA_A receptors: Insights on etifoxine | journal = The World Journal of Biological Psychiatry | volume = 19 | issue = sup1 | pages = S36–S45 | date = 11 September 2018 | pmid = 30204559 | doi = 10.1080/15622975.2018.1468030 | doi-access = free }}</ref> Bromazepam is an intermediate-acting benzodiazepine, is moderately [[lipophilic]] compared to other substances of its class<ref>{{cite journal | vauthors = Adeyemo MA, Idowu SO |title=Correlation of lipophilicity descriptors with pharmacokinetic parameters of selected benzodiazepines |journal=African Journal of Biomedical Research |date=25 November 2016 |volume=19 |issue=3 |pages=213–218 |url=https://www.ajol.info/index.php/ajbr/article/view/150280 }}</ref> and metabolised hepatically via oxidative pathways.<ref>{{cite journal | vauthors = Oelschläger H | title = [Chemical and pharmacologic aspects of benzodiazepines] | language = German | journal = Schweizerische Rundschau für Medizin Praxis | volume = 78 | issue = 27–28 | pages = 766–772 | date = July 1989 | pmid = 2570451 }}</ref> It does not possess any antidepressant or antipsychotic qualities.<ref>{{cite journal | vauthors = Amphoux G, Agussol P, Girard J | title = [The action of bromazepam on anxiety (author's transl)] | language = French | journal = La Nouvelle Presse Médicale | volume = 11 | issue = 22 | pages = 1738–1740 | date = May 1982 | pmid = 6124947 | trans-title = The action of bromazepam on anxiety }}</ref>

After night time administration of bromazepam a highly significant reduction of gastric acid secretion occurs during sleep followed by a highly significant rebound in gastric acid production the following day.<ref>{{cite journal | vauthors = Stacher G, Stärker D | title = Inhibitory effect of bromazepam on basal and betazole-stimulated gastric acid secretion in man | journal = Gut | volume = 15 | issue = 2 | pages = 116–120 | date = February 1974 | pmid = 4820635 | pmc = 1412901 | doi = 10.1136/gut.15.2.116 }}</ref>

Bromazepam alters the electrical status of the brain causing an increase in beta activity and a decrease in alpha activity in EEG recordings.<ref>{{cite journal | vauthors = Fink M, Weinfeld RE, Schwartz MA, Conney AH | title = Blood levels and electroencephalographic effects of diazepam and bromazepam | journal = Clinical Pharmacology and Therapeutics | volume = 20 | issue = 2 | pages = 184–191 | date = August 1976 | pmid = 7375 | doi = 10.1002/cpt1976202184 | s2cid = 38155674 }}</ref>

===Pharmacokinetics===

Bromazepam is reported to be metabolized by a hepatic enzyme belonging to the [[Cytochrome P450]] family of enzymes. In 2003, a team led by Oda Manami at [[Oita Medical University]] reported that [[CYP3A4]], a member of the Cytochrome P450 family, was not the responsible enzyme since [[itraconazole]], a known inhibitor of CYP3A4, did not affect its metabolism.<ref name="itraconazole">{{cite journal | vauthors = Oda M, Kotegawa T, Tsutsumi K, Ohtani Y, Kuwatani K, Nakano S | title = The effect of itraconazole on the pharmacokinetics and pharmacodynamics of bromazepam in healthy volunteers | journal = European Journal of Clinical Pharmacology | volume = 59 | issue = 8–9 | pages = 615–619 | date = November 2003 | pmid = 14517708 | doi = 10.1007/s00228-003-0681-4 | s2cid = 24131632 }}</ref> In 1995, J. van Harten at the [[Solvay Pharmaceutical]] Department of Clinical Pharmacology in [[Weesp]] reported that [[fluvoxamine]], which is a potent inhibitor of CYP1A2, a less potent [[CYP3A4]] inhibitor, and a negligible inhibitor of [[CYP2D6]], does inhibit its metabolism.<ref name="pmid8846617" />

The major metabolite of bromazepam is hydroxybromazepam,<ref name="itraconazole"/> which is an active agent too and has a half-life approximately equal to that of bromazepam.{{citation needed|date=April 2009}}

Bromazepam is similar in side effects to other benzodiazepines. The most common side effects reported are drowsiness, sedation, [[ataxia]], memory impairment, and dizziness.<ref name=RxMed>{{cite web|title=LECTOPAM®|url=http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20%28General%20Monographs-%20L%29/LECTOPAM.html|work=RxMed|access-date=23 March 2014}}</ref> Impairments to memory functions are common with bromazepam and include a reduced [[working memory]] and reduced ability to process environmental information.<ref>{{cite journal | vauthors = Münte TF, Gehde E, Johannes S, Seewald M, Heinze HJ | title = Effects of alprazolam and bromazepam on visual search and verbal recognition memory in humans: a study with event-related brain potentials | journal = Neuropsychobiology | volume = 34 | issue = 1 | pages = 49–56 | year = 1996 | pmid = 8884760 | doi = 10.1159/000119291 }}</ref><ref>{{cite journal | vauthors = Montenegro M, Veiga H, Deslandes A, Cagy M, McDowell K, Pompeu F, Piedade R, Ribeiro P | display-authors = 6 | title = [Neuromodulatory effects of caffeine and bromazepam on visual event-related potential (P300): a comparative study] | journal = Arquivos de Neuro-Psiquiatria | volume = 63 | issue = 2B | pages = 410–415 | date = June 2005 | pmid = 16059590 | doi = 10.1590/s0004-282x2005000300009 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Cunha M, Portela C, Bastos VH, Machado D, Machado S, Velasques B, Budde H, Cagy M, Basile L, Piedade R, Ribeiro P | display-authors = 6 | title = Responsiveness of sensorimotor cortex during pharmacological intervention with bromazepam | journal = Neuroscience Letters | volume = 448 | issue = 1 | pages = 33–36 | date = December 2008 | pmid = 18938214 | doi = 10.1016/j.neulet.2008.10.024 | s2cid = 22491979 }}</ref> A 1975 experiment on healthy, male college students exploring the effects of four different drugs on learning capacity observed that taking bromazepam alone at 6&nbsp;mg 3 times daily for 2 weeks impaired learning capacities significantly. In combination with alcohol, impairments in learning capacity became even more pronounced.<ref>{{cite journal | vauthors = Liljequist R, Linnoila M, Mattila MJ, Saario I, Seppälä T | title = Effect of two weeks' treatment with thioridazine, chlorpromazine, sulpiride and bromazepam, alone or in combination with alcohol, on learning and memory in man | journal = Psychopharmacologia | volume = 44 | issue = 2 | pages = 205–208 | date = October 1975 | pmid = 710 | doi = 10.1007/BF00421011 | s2cid = 36415883 }}</ref> Various studies report impaired memory, visual information processing and sensory data and impaired psychomotor performance;<ref>{{cite journal | vauthors = Stacher G, Bauer P, Brunner H, Grünberger J | title = Gastric acid secretion, serum-gastrin levels and psychomotor function under the influence of placebo, insulin-hypoglycemia, and/or bromazepam | journal = International Journal of Clinical Pharmacology and Biopharmacy | volume = 13 | issue = 1 | pages = 1–10 | date = January 1976 | pmid = 2560 }}</ref><ref>{{cite journal | vauthors = Bourin M, Auget JL, Colombel MC, Larousse C | title = Effects of single oral doses of bromazepam, buspirone and clobazam on performance tasks and memory | journal = Neuropsychobiology | volume = 22 | issue = 3 | pages = 141–145 | date = 1989 | pmid = 2577220 | doi = 10.1159/000118609 }}</ref><ref>{{cite journal | vauthors = Puga F, Sampaio I, Veiga H, Ferreira C, Cagy M, Piedade R, Ribeiro P | title = The effects of bromazepam on the early stage of visual information processing (P100) | journal = Arquivos de Neuro-Psiquiatria | volume = 65 | issue = 4A | pages = 955–959 | date = December 2007 | pmid = 18094853 | doi = 10.1590/s0004-282x2007000600006 | doi-access = free }}</ref> deterioration of cognition including attention capacity and impaired co-ordinative skills;<ref>{{cite journal | vauthors = Saario I | title = Psychomotor skills during subacute treatment with thioridazine and bromazepam, and their combined effects with alcohol | journal = Annals of Clinical Research | volume = 8 | issue = 2 | pages = 117–123 | date = April 1976 | pmid = 7178 }}</ref><ref>{{cite journal | vauthors = Jansen AA, Verbaten MN, Slangen JL | title = Acute effects of bromazepam on signal detection performance, digit symbol substitution test and smooth pursuit eye movements | journal = Neuropsychobiology | volume = 20 | issue = 2 | pages = 91–95 | year = 1988 | pmid = 2908134 | doi = 10.1159/000118481 }}</ref> impaired reactive and attention performance, which can impair driving skills;<ref>{{cite book |doi=10.1159/000399456 |chapter=Two Weeks' Treatment with Chlorpromazine, Thioridazine, Sulpiride, or Bromazepam: Actions and Interactions with Alcohol on Psychomotor Skills Related to Driving |title=Alcohol, Drugs and Driving |series=Modern Trends in Pharmacopsychiatry |year=1976 | vauthors = Seppälä T, Saario I, Mattila MJ |volume=11 |pages=85–90 |pmid=9581 |isbn=978-3-8055-2349-3 }}</ref> [[drowsiness]] and decrease in [[libido]].<ref>{{cite journal | vauthors = Horseau C, Brion S | title = [Clinical trial of bromazepam. Thirty-four cases (author's transl)] | language = French | journal = La Nouvelle Presse Médicale | volume = 11 | issue = 22 | pages = 1741–1743 | date = May 1982 | pmid = 6124948 }}</ref><ref>{{cite journal | vauthors = Perret J, Zagala A, Gaio JM, Hommel M, Meaulle F, Pellat J, Pollak P | title = [Bromazepam in anxiety. Clinical evaluation (author's transl)] | language = French | journal = La Nouvelle Presse Médicale | volume = 11 | issue = 22 | pages = 1722–1724 | date = May 1982 | pmid = 6124942 }}</ref> Unsteadiness after taking bromazepam is, however, less pronounced than other benzodiazepines such as [[lorazepam]].<ref>{{cite journal | vauthors = Patat A, Foulhoux P | title = Effect on postural sway of various benzodiazepine tranquillizers | journal = British Journal of Clinical Pharmacology | volume = 20 | issue = 1 | pages = 9–16 | date = July 1985 | pmid = 2862898 | pmc = 1400619 | doi = 10.1111/j.1365-2125.1985.tb02792.x }}</ref>

On occasion, benzodiazepines can induce extreme alterations in memory such as [[anterograde amnesia]] and [[amnesic automatism]], which may have medico-legal consequences. Such reactions occur usually only at the higher dose end of the prescribing spectrum.<ref>{{cite journal | vauthors = Rager P, Bénézech M | title = [Memory gaps and hypercomplex automatisms after a single oral dose of benzodiazepines: clinical and medico-legal aspects] | language = French | journal = Annales Médico-Psychologiques | volume = 144 | issue = 1 | pages = 102–109 | date = January 1986 | pmid = 2876672 | trans-title = Memory gaps and hypercomplex automatisms after a single oral dose of benzodiazepines: clinical and medico-legal aspects }}</ref>

Very rarely, [[dystonia]] can develop.<ref>{{cite journal | vauthors = Pérez Trullen JM, Modrego Pardo PJ, Vázquez André M, López Lozano JJ | title = Bromazepam-induced dystonia | journal = Biomedicine & Pharmacotherapy | volume = 46 | issue = 8 | pages = 375–376 | date = January 1992 | pmid = 1292648 | doi = 10.1016/0753-3322(92)90306-r }}</ref>

Leukopenia and liver-damage of the type with or without jaundice (icterus) have additionally been seen; the original manufacturer [[Hoffmann-La Roche|Roche]] recommends regular laboratory examinations to be performed routinely.

Ambulatory patients should be warned that may impair the ability to drive vehicles and to operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants. During the course of therapy, tolerance to the sedative effect usually develops.

===Frequency and seriousness of adverse effects===

As with all medication, the frequency and seriousness of side-effects varies greatly depending on quantities consumed.<ref>{{Cite web | url=https://www.doctissimo.fr/medicament-LEXOMIL.htm | title=LEXOMIL - Bromazépam - Posologie, Effets secondaires, Grossesse}}</ref><ref>{{Cite web | url=https://www.drugs.com/article/drug-side-effects.html |title = How to Manage Common Drug Side Effects}}</ref> In a study about bromazepam's negative effects on psychomotor skills and driving ability, it was noted that 3&nbsp;mg doses caused minimal impairment.<ref>{{cite journal | vauthors = Hobi V, Dubach UC, Skreta M, Forgo I, Riggenbach H | title = The subacute effect of bromazepam on psychomotor activity and subjective mood | journal = The Journal of International Medical Research | volume = 10 | issue = 3 | pages = 140–146 | date = 25 June 2016 | pmid = 6124470 | doi = 10.1177/030006058201000302 | s2cid = 25165191 }}</ref> It also appeared that impairment may be tied to methods of testing more so than on the product's intrinsic activity.<ref>{{cite journal | vauthors = Hobi V, Dubach UC, Skreta M, Forgo J, Riggenbach H | title = The effect of bromazepam on psychomotor activity and subjective mood | journal = The Journal of International Medical Research | volume = 9 | issue = 2 | pages = 89–97 | date = 25 June 2016 | pmid = 6112173 | doi = 10.1177/030006058100900201 | s2cid = 21899896 }}</ref>

Moreover, side-effects other than drowsiness, dizziness and ataxia seem to be rare<ref>{{Cite web | url=http://sideeffects.embl.de/drugs/2441/ |title = Side effect information for Bromazepam}}</ref> and not experienced by more than a few percent of users. The use of other, comparable medication seems to display an identically moderate side-effect profile.<ref>{{Cite web | url=http://sideeffects.embl.de/drugs/3958/ |title = Side effect information for Lorazepam}}</ref><ref>{{Cite web | url=http://sideeffects.embl.de/drugs/3016/ |title = Side effect information for Diazepam}}</ref><ref>{{Cite web | url=http://base-donnees-publique.medicaments.gouv.fr/affichageDoc.php?specid=62505828&typedoc=N |title=Notice patient - LORAZEPAM MYLAN 1 mg, comprimé pelliculé sécable - Base de données publique des médicaments}}</ref>

===Tolerance, dependence and withdrawal===

Prolonged use of bromazepam can cause tolerance and may lead to both physical and psychological dependence on the drug, and as a result, it is a medication which is controlled by international law. It is nonetheless important to note that dependence, long-term use and misuse occur in a minority of cases<ref>{{cite journal | vauthors = Yen CF, Ko CH, Chang YP, Yu CY, Huang MF, Yeh YC, Lin JJ, Chen CS | display-authors = 6 | title = Dependence, misuse, and beliefs regarding use of hypnotics by elderly psychiatric patients taking zolpidem, estazolam, or flunitrazepam | journal = Asia-Pacific Psychiatry | volume = 7 | issue = 3 | pages = 298–305 | date = September 2015 | pmid = 25296384 | doi = 10.1111/appy.12147 | s2cid = 5782780 }}</ref><ref>{{cite journal | vauthors = Schmidt LG, Grohmann R, Müller-Oerlinghausen B, Otto M, Rüther E, Wolf B | title = Prevalence of benzodiazepine abuse and dependence in psychiatric in-patients with different nosology. An assessment of hospital-based drug surveillance data | journal = The British Journal of Psychiatry | volume = 154 | issue = 6 | pages = 839–843 | date = June 1989 | pmid = 2574611 | doi = 10.1192/bjp.154.6.839 | s2cid = 10441280 }}</ref><ref>{{cite journal | vauthors = Airagnes G, Lemogne C, Renuy A, Goldberg M, Hoertel N, Roquelaure Y, Limosin F, Zins M | display-authors = 6 | title = Prevalence of prescribed benzodiazepine long-term use in the French general population according to sociodemographic and clinical factors: findings from the CONSTANCES cohort | journal = BMC Public Health | volume = 19 | issue = 1 | pages = 566 | date = May 2019 | pmid = 31088561 | pmc = 6518636 | doi = 10.1186/s12889-019-6933-8 | doi-access = free }}</ref> and are not representative of most patients' experience with this type of medication.<ref name="pmid28614686">{{cite journal | vauthors = Soyka M | title = Treatment of Benzodiazepine Dependence | journal = The New England Journal of Medicine | volume = 376 | issue = 24 | pages = 2399–2400 | date = June 2017 | pmid = 28614686 | doi = 10.1056/NEJMc1705239 | url = http://www.dickyricky.com/Medicine/Papers/2017_03_23%20NEJM%20Treatment%20of%20Benzodiazepine%20Dependence.pdf }}</ref><ref>{{Cite web | author = HealthDay News | work = Psychiatry Advisor | publisher = Haymarket | url= https://www.psychiatryadvisor.com/home/topics/anxiety/prevalence-of-benzodiazepine-use-12-6-percent-in-the-united-states/ |title = Prevalence of Benzodiazepine Use 12.6 Percent in the United States|date = 3 January 2019}}</ref>

It shares with other benzodiazepines the risk of abuse, misuse, [[Substance dependence|psychological dependence]] or [[physical dependence]].<ref>{{cite journal | vauthors = Rastogi RB, Lapierre YD, Singhal RL | title = Some neurochemical correlates of "rebound" phenomenon observed during withdrawal after long-term exposure to 1, 4-benzodiazepines | journal = Progress in Neuro-Psychopharmacology | volume = 2 | issue = 1 | pages = 43–54 | year = 1978 | pmid = 31644 | doi = 10.1016/0364-7722(78)90021-8 }}</ref><ref>{{cite journal | vauthors = Laux G | title = [A case of Lexotanil dependence. Case report on tranquilizer abuse] | journal = Der Nervenarzt | volume = 50 | issue = 5 | pages = 326–327 | date = May 1979 | pmid = 37451 }}</ref> A withdrawal study demonstrated both psychological dependence and physical dependence on bromazepam including marked [[rebound anxiety]] after 4 weeks chronic use. Those whose dose was gradually reduced experienced no withdrawal.<ref>{{cite journal | vauthors = Fontaine R, Chouinard G, Annable L | title = Rebound anxiety in anxious patients after abrupt withdrawal of benzodiazepine treatment | journal = The American Journal of Psychiatry | volume = 141 | issue = 7 | pages = 848–852 | date = July 1984 | pmid = 6145363 | doi = 10.1176/ajp.141.7.848 }}</ref>

Patients treated with bromazepam for generalised anxiety disorder were found to experience withdrawal symptoms such as a worsening of anxiety, as well as the development of physical withdrawal symptoms when abruptly withdrawn bromazepam.<ref>{{cite journal | vauthors = Chouinard G, Labonte A, Fontaine R, Annable L | title = New concepts in benzodiazepine therapy: rebound anxiety and new indications for the more potent benzodiazepines | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 7 | issue = 4–6 | pages = 669–673 | year = 1983 | pmid = 6141609 | doi = 10.1016/0278-5846(83)90043-X | s2cid = 32967696 }}</ref> Abrupt or over rapid withdrawal from bromazepam after chronic use even at therapeutic prescribed doses can lead to a severe withdrawal syndrome including [[status epilepticus]] and a condition resembling [[delerium tremens]].<ref>{{cite journal | vauthors = Böning J | title = [Bromazepam withdrawal delirium - a psychopharmacological contribution to clinical withdrawal syndromes (author's transl)] | journal = Der Nervenarzt | volume = 52 | issue = 5 | pages = 293–297 | date = May 1981 | pmid = 6113557 }}</ref><ref>{{cite journal | vauthors = Thomas P, Lebrun C, Chatel M | title = De novo absence status epilepticus as a benzodiazepine withdrawal syndrome | journal = Epilepsia | volume = 34 | issue = 2 | pages = 355–358 | date = March 1993 | pmid = 8384109 | doi = 10.1111/j.1528-1157.1993.tb02421.x | s2cid = 45915803 }}</ref><ref>{{cite journal | vauthors = Fukuda M, Nakajima N, Tomita M | title = Generalized tonic-clonic seizures following withdrawal of therapeutic dose of bromazepam | journal = Pharmacopsychiatry | volume = 32 | issue = 1 | pages = 42–43 | date = January 1999 | pmid = 10071183 | doi = 10.1055/s-2007-979188 | s2cid = 260238907 }}</ref>

Animal studies have shown that chronic administration of [[diazepam]] (or bromazepam) causes a decrease in spontaneous locomotor activity, decreased turnover of [[noradrenaline]] and dopamine and [[serotonin]], increased activity of tyrosine hydroxylase and increased levels of the catecholamines. During withdrawal of bromazepam or diazepam a fall in tryptophan, serotonin levels occurs as part of the [[benzodiazepine withdrawal syndrome]].<ref>{{cite journal | vauthors = Agarwal RA, Lapierre YD, Rastogi RB, Singhal RL | title = Alterations in brain 5-hydroxytryptamine metabolism during the 'withdrawal' phase after chronic treatment with diazepam and bromazepam | journal = British Journal of Pharmacology | volume = 60 | issue = 1 | pages = 3–9 | date = May 1977 | pmid = 18243 | pmc = 1667179 | doi = 10.1111/j.1476-5381.1977.tb16740.x }}</ref> Changes in the levels of these chemicals in the brain can cause headaches, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, [[dysphoria]], dizziness, [[derealization]], depersonalization, numbness/tingling of extremities, hypersensitivity to light, sound, and smell, perceptual distortions, nausea, vomiting, diarrhea, appetite loss, hallucinations, delirium, seizures, tremor, stomach cramps, [[myalgia]], agitation, palpitations, [[tachycardia]], panic attacks, short-term memory loss, and hyperthermia.<ref name="ashman">{{cite web | author= Professor Heather Ashton | year= 2002 | url= http://benzo.org.uk/manual/index.htm | title= Benzodiazepines: How They Work and How to Withdraw }}</ref><ref>{{cite journal | vauthors = O'Connor RD | title = Benzodiazepine dependence--a treatment perspective and an advocacy for control | journal = NIDA Research Monograph | volume = 131 | pages = 266–269 | year = 1993 | pmid = 8105385 }}</ref>

====

{{main article|Benzodiazepine overdose}}

Bromazepam is commonly involved in drug overdoses.<ref>{{cite journal | vauthors = Gandolfi E, Andrade M | title = [Drug-related toxic events in the state of São Paulo, Brazil] | language = Portuguese | journal = Revista de Saude Publica | volume = 40 | issue = 6 | pages = 1056–1064 | date = December 2006 | pmid = 17173163 | doi = 10.1590/s0034-89102006000700014 | trans-title = Drug-related toxic events in the state of São Paulo, Brazil | doi-access = free }}</ref> A severe bromazepam [[benzodiazepine overdose]] may result in an alpha pattern coma type.<ref>{{cite journal | vauthors = Pasinato E, Franciosi A, De Vanna M | title = ["Alpha pattern coma" after poisoning with flunitrazepam and bromazepam. Case description] | journal = Minerva Psichiatrica | volume = 24 | issue = 2 | pages = 69–74 | date = 1983 | pmid = 6140613 }}</ref> The toxicity of bromazepam in overdosage increases when combined with other CNS depressant drugs such as [[ethanol|alcohol]] or sedative hypnotic drugs.<ref>{{cite journal | vauthors = Marrache F, Mégarbane B, Pirnay S, Rhaoui A, Thuong M | title = Difficulties in assessing brain death in a case of benzodiazepine poisoning with persistent cerebral blood flow | journal = Human & Experimental Toxicology | volume = 23 | issue = 10 | pages = 503–505 | date = October 2004 | pmid = 15553176 | doi = 10.1191/0960327104ht478cr | s2cid = 19380042 | doi-access = free | bibcode = 2004HETox..23..503M }}</ref> Similarly to other benzodiazepines however, being a positive modulator of certain neuroreceptors and not an [[agonist]], the product has reduced overdose potential compared to older products of the [[barbiturate]] class. Its consumption alone is very seldom fatal in healthy adults.<ref>{{cite journal | vauthors = Löscher W, Rogawski MA | title = How theories evolved concerning the mechanism of action of barbiturates | journal = Epilepsia | volume = 53 | issue = Suppl 8 | pages = 12–25 | date = December 2012 | pmid = 23205959 | doi = 10.1111/epi.12025 | s2cid = 4675696 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Koyama K, Shimazu Y, Kikuno T, Kaziwara H, Sekiguti H | title = [Pharmacokinetics of bromazepam in 57 patients with acute drug intoxication] | language = Japanese | journal = Chudoku Kenkyu | volume = 16 | issue = 1 | pages = 51–56 | date = January 2003 | pmid = 12712542 | trans-title = Pharmacokinetics of bromazepam in 57 patients with acute drug intoxication }}</ref>

Bromazepam was in 2005 the most common benzodiazepine involved in intentional overdoses in [[France]].<ref>{{cite journal | vauthors = Staikowsky F, Theil F, Candella S | title = [Trends in the pharmaceutical profile of intentional drug overdoses seen in the emergency room] | language = French | journal = Presse Médicale | volume = 34 | issue = 12 | pages = 842–846 | date = July 2005 | pmid = 16097205 | doi = 10.1016/s0755-4982(05)84060-6 | trans-title = Trends in the pharmaceutical profile of intentional drug overdoses seen in the emergency room }}</ref> Bromazepam has also been responsible for accidental poisonings in companion animals. A review of benzodiazepine poisonings in cats and dogs from 1991 to 1994 found bromazepam to be responsible for significantly more poisonings than any other benzodiazepine.<ref name=Bertini>{{cite journal | vauthors = Bertini S, Buronfosse F, Pineau X, Berny P, Lorgue G | title = Benzodiazepine poisoning in companion animals | journal = Veterinary and Human Toxicology | volume = 37 | issue = 6 | pages = 559–562 | date = December 1995 | pmid = 8588297 }}</ref>

==Contraindications==

Benzodiazepines require special precaution if used in elderly, pregnant, child, alcohol- or drug-dependent individuals and individuals with [[comorbid]] [[psychiatric disorders]].<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>

===Special populations===

*Globally, bromazepam is contraindicated and should be used with caution in women who are pregnant, the elderly, patients with a history of alcohol or other substance abuse disorders and children.

*In 1987, a team of scientists led by Ochs reported that the elimination half-life, peak [[Wiktionary:serum concentration|serum concentration]], and [[Wiktionary:serum free fraction|serum free fraction]] are significantly elevated and the [[Wiktionary:oral clearance|oral clearance]] and [[volume of distribution]] significantly lowered in elderly subjects.<ref name="bromazepamold">{{cite journal | vauthors = Ochs HR, Greenblatt DJ, Friedman H, Burstein ES, Locniskar A, Harmatz JS, Shader RI | title = Bromazepam pharmacokinetics: influence of age, gender, oral contraceptives, cimetidine, and propranolol | journal = Clinical Pharmacology and Therapeutics | volume = 41 | issue = 5 | pages = 562–570 | date = May 1987 | pmid = 2882883 | doi = 10.1038/clpt.1987.72 | s2cid = 1099919 }}</ref> The clinical consequence is that the elderly should be treated with lower doses than younger patients.

*Bromazepam may affect driving and ability to operate machinery.<ref>{{cite journal | vauthors = Hobi V, Kielholz P, Dubach UC | title = [The effect of bromazepam on fitness to drive (author's transl)] | language = German | journal = Munchener Medizinische Wochenschrift | volume = 123 | issue = 42 | pages = 1585–1588 | date = October 1981 | pmid = 6118830 | trans-title = The effect of bromazepam on fitness to drive }}</ref>

*Bromazepam is [[pregnancy category]] D, a classification that means that bromazepam has been shown to cause harm to the unborn child. The [[Hoffman LaRoche]] product information leaflet warns against breast feeding while taking bromazepam. There has been at least one report of [[sudden infant death syndrome]] linked to [[breast feeding]] while consuming bromazepam.<ref>{{cite web | url = http://www.roche-australia.com/downloads/lexotan-pi.cfm?action=get | title = NAME OF THE MEDICINE LEXOTAN | access-date = 16 December 2008 | author = Hoffman LaRoche Pharmaceuticals | authorlink = Hoffman LaRoche | date = 3 April 2008 | format = PDF | publisher = roche-australia.com | location = Australia |archive-url = https://web.archive.org/web/20080719012817/http://www.roche-australia.com/downloads/lexotan-pi.cfm?action=get <!-- Bot retrieved archive --> |archive-date = 19 July 2008}}</ref><ref>{{cite journal | vauthors = Martens PR | title = A sudden infant death like syndrome possibly induced by a benzodiazepine in breast-feeding | journal = European Journal of Emergency Medicine | volume = 1 | issue = 2 | pages = 86–87 | date = June 1994 | pmid = 9422145 | doi = 10.1097/00063110-199406000-00008 }}</ref>

== Interactions ==

[[Cimetidine]], [[fluvoxamine]] and [[propranolol]] causes a marked increase in the [[Biological half-life|elimination half-life]] of bromazepam leading to increased accumulation of bromazepam.<ref name="bromazepamold"/><ref>{{cite journal | vauthors = Perucca E, Gatti G, Spina E | title = Clinical pharmacokinetics of fluvoxamine | journal = Clinical Pharmacokinetics | volume = 27 | issue = 3 | pages = 175–190 | date = September 1994 | pmid = 7988100 | doi = 10.2165/00003088-199427030-00002 | s2cid = 22472247 }}</ref><ref name="pmid8846617">{{cite journal | vauthors = van Harten J | title = Overview of the pharmacokinetics of fluvoxamine | journal = Clinical Pharmacokinetics | volume = 29| issue = Suppl 1 | pages = 1–9 | year = 1995 | pmid = 8846617 | doi = 10.2165/00003088-199500291-00003 | s2cid = 71812133 }}</ref>

==Society and culture==

==Drug misuse==

{{See also|Benzodiazepine }}

Bromazepam has a similar misuse risk as other benzodiazepines such as [[diazepam]].<ref>{{cite journal | = Woods |title=Progress report on the stimulant-depressant abuse liability evaluation project |= |= |pages=59–62 |= |= |= }}</ref> In [[France]] car accidents involving psychotropic drugs in combination found benzodiazepines, mainly [[diazepam]], [[nordiazepam]], and bromazepam, to be the most common drug, almost twice that of the nextmostcommon drug [[cannabis]].<ref>{{cite journal | = Staub C, Lacalle H, Fryc O | title = [Presence of psychotropic drugs in the blood of drivers responsible for car accidents, and who consumed alcohol at the same time] | language = French | journal = | volume = 39 | issue = 3 | pages = | = 1994 | pmid = 8048274 }}</ref> Bromazepam has also been used serious criminal offences including [[robbery]], [[homicide]] and [[sexual ]].<ref>{{cite journal | = Brinkmann B Fechner G Püschel K |title=Identification of mechanical asphyxiation in cases of attempted masking of the homicide |volume=26 |issue=4 |pages= |= | |doi=10.1016/0379-0738(84)90028-8 }}</ref><ref>{{cite journal |=de Boisjolly JM, Rougé-Maillart C, Roy PM, Roussel B, Turcant A, Delhumeau A |title=[Chemical submission] |language=French |journal=Presse |volume=32 |issue=26 |pages = |=August |pmid=14506459 |-}}</ref><ref>{{cite journal |=Djezzar S, Questel F, Burin E, Dally S |title=Chemical submission: results of 4-year French inquiry |journal= Legal |volume= 123|issue= 3|pages = |= |pmid=18925406 |doi=10.1007/s00414-008-0291-x |= |=}}</ref>

== ==

It is marketed under several brand names, including, Brozam, Lectopam, [https://edrug-online.com/342/lexomil-tablet.html Lexomil], Lexotan, Lexilium, Lexaurin, Brazepam, Rekotnil, Bromaze, Somalium, Lexatin, Calmepam, Zepam and Lexotanil.<ref>{{cite web| url=http://www.non-benzodiazepines.org.uk/benzodiazepine-names.html| title=Benzodiazepine Names| access-date=2008-10-31| publisher=non-benzodiazepines.org.uk| url-status=dead| archive-url=https://web.archive.org/web/20081208054743/http://www.non-benzodiazepines.org.uk/benzodiazepine-names.html| archive-date=2008-12-08}}</ref><!-- Do not add any more brand names to this list unless they are from English-speaking countries for this wikipedia english version of the bromazepam article. There are dozens upon dozens of brand names if all non-English-speaking countries are included. -->

== ==

Bromazepam is a [[Convention on Psychotropic Substances#Schedules of Controlled Substances|Schedule IV]] drug under the [[Convention on Psychotropic Substances]].<ref name="schedule4">[http://www.incb.org/pdf/e/list/green.pdf List of psychotropic substances under international control] {{webarchive |url=https://web.archive.org/web/20051205125434/http://www.incb.org/pdf/e/list/green.pdf |date=December 5, 2005 }} (PDF). International Narcotics Control Board.</ref>

===Synthesis===

<div style="width:auto; overflow:scroll">

[[File:Bromazepam synthesis.png|thumb|center|700px|Bromazepam synthesis.<ref>{{cite web|url=http://drugsynthesis.blogspot.com/2012/01/laboratory-synthesis-of-bromazepam.html|title=Synthesis Of Drugs: Laboratory Synthesis Of Bromazepam|last=Sanal|date=8 January 2012}}</ref>]]

</div>

== See also ==

==References==

==External links==

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