Clonazepam: Difference between revisions

{{Short description|Benzodiazepine medication}}

{{Distinguish|clozapine|clonazolam|clorazolam}}

{{Use dmy dates|date=October 2021}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 458436513

| imageL = Clonazepam 200.svg

| widthL = 150

| altL =

| imageR = Clonazepam ball-and-stick model.png

| widthR = 150

| altR = <!-- Clinical data -->

| pronounce = kləˈnazɪpam, kloe-NAZ-e-pam

| tradename = Klonopin, Rivotril, Paxam,<ref name="Paxam_Data_Sheet" /> others<ref name="Clonazepam International">{{cite news|title=Clonazepam International|url=https://www.drugs.com/international/clonazepam.html|newspaper=Drugs.com|url-status=live|archive-url=https://web.archive.org/web/20170825060941/https://www.drugs.com/international/clonazepam.html|archive-date=25 August 2017}}</ref>

| Drugs.com = {{drugs.com|monograph|clonazepam}}

| MedlinePlus = a682279

| DailyMedID = Clonazepam

| pregnancy_AU = B3

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Clonazepam Use During Pregnancy | website=Drugs.com | date=4 May 2020 | url=https://www.drugs.com/pregnancy/clonazepam.html | access-date=17 May 2020 | archive-date=28 July 2020 | archive-url=https://web.archive.org/web/20200728161048/https://www.drugs.com/pregnancy/clonazepam.html | url-status=live }}</ref>

| pregnancy_category =

| dependency_liability = [[Physical dependence|Physical]]: Very High

[[Psychological dependence|Psychological]]: Moderate

| addiction_liability = Moderate<ref name="longo2000">{{cite journal | vauthors = Longo LP, Johnson B | title = Addiction: Part I. Benzodiazepines--side effects, abuse risk and alternatives | journal = American Family Physician | volume = 61 | issue = 7 | pages = 2121–2128 | date = April 2000 | pmid = 10779253 | url = https://www.aafp.org/pubs/afp/issues/2000/0401/p2121.html | access-date = 11 December 2022 | archive-date = 12 May 2008 | archive-url = https://web.archive.org/web/20080512180747/http://www.aafp.org/afp/20000401/2121.html | url-status = live }}</ref><ref>{{cite book | vauthors = Hupp JR, Tucker MR, Ellis E |title=Contemporary Oral and Maxillofacial Surgery - E-Book |date=2013 |publisher=Elsevier Health Sciences |isbn=9780323226875 |page=679 |url=https://books.google.com/books?id=RcbsAwAAQBAJ&pg=PA679 }}</ref>

| routes_of_administration = [[Oral administration|oral]], [[Intramuscular injection|intramuscular]], [[Intravenous therapy|intravenous]], [[Sublingual administration|sublingual]]

| class = [[Benzodiazepine]]

| ATC_prefix = N03

| ATC_suffix = AE01

| ATC_supplemental = <!-- Legal status -->

| legal_AU = S4

| legal_AU_comment =

| legal_BR = B1

| legal_BR_comment =

| legal_CA = Schedule IV

| legal_CA_comment =

| legal_DE = Rx-only/Anlage III

| legal_DE_comment =

| legal_NZ = Class C

| legal_NZ_comment =

| legal_UK = Class C

| legal_UK_comment =

| legal_US = Schedule IV

| legal_US_comment =

| legal_EU =

| legal_EU_comment =

| legal_UN = Psychotropic Schedule IV

| legal_UN_comment =

| legal_status = Rx-only

<!-- Pharmacokinetic data -->| bioavailability = 90%

| protein_bound = ≈85%

| metabolism = [[Liver]] ([[CYP3A]])<ref name=AHFS2015/>

| metabolites = 7-aminoclonazepam<br>

7-acetaminoclonazepam<br>3-hydroxy clonazepam<ref name="auto">{{cite journal | vauthors = Ebel S, Schütz H | title = [Studies on the detection of clonazepam and its main metabolites considering in particular thin-layer chromatography discrimination of nitrazepam and its major metabolic products (author's transl)] | journal = Arzneimittel-Forschung | volume = 27 | issue = 2 | pages = 325–337 | date = February 1977 | pmid = 577149 }}</ref><ref>{{cite journal | vauthors = Steentoft A, Linnet K | title = Blood concentrations of clonazepam and 7-aminoclonazepam in forensic cases in Denmark for the period 2002-2007 | journal = Forensic Science International | volume = 184 | issue = 1–3 | pages = 74–79 | date = January 2009 | pmid = 19150586 | doi = 10.1016/j.forsciint.2008.12.004 }}</ref>

| onset = Within an hour<ref name=Coop2007/>

| elimination_half-life = 19–60 hours<ref name="Riss-2008"/>

| duration_of_action = 8–12 hours<ref name=Coop2007/><ref name="Paxam_Data_Sheet" />

| excretion = [[Kidney]]

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

| CAS_number = 1622-61-3

| CAS_supplemental =

| PubChem = 2802

| IUPHAR_ligand = 6963

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

| DrugBank = DB01068

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

| ChemSpiderID = 2700

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

| UNII = 5PE9FDE8GB

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

| KEGG = D00280

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 3756

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

| ChEMBL = 452

| NIAID_ChemDB =

| PDB_ligand =

| synonyms = <!-- Chemical and physical data -->

| IUPAC_name = 5-(2-Chlorophenyl)-7-nitro-1,3-dihydro-1,4-benzodiazepin-2-one

| C = 15

| H = 10

| Cl = 1

| N = 3

| O = 3

| SMILES = O=C1CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1

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

| StdInChI = 1S/C15H10ClN3O3/c16-12-4-2-1-3-10(12)15-11-7-9(19(21)22)5-6-13(11)18-14(20)8-17-15/h1-7H,8H2,(H,18,20)

| StdInChI_comment =

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

| StdInChIKey = DGBIGWXXNGSACT-UHFFFAOYSA-N

| density =

| density_notes =

| melting_point =

| melting_high =

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility =

| sol_units =

| specific_rotation =

<!-- Definition and uses -->

'''Clonazepam''', sold under the brand names '''Klonopin''' and '''Rivotril''', is a [[medication]] used to prevent and treat [[anxiety disorder]]s, [[seizure]]s, [[Bipolar disorder|bipolar]] [[mania]], agitation associated with [[psychosis]], [[Obsessive–compulsive disorder|OCD]] and [[akathisia]].<ref name="AHFS2015">{{cite web |title=Clonazepam |url=https://www.drugs.com/monograph/clonazepam.html |publisher=The American Society of Health-System Pharmacists |access-date=15 August 2015 |url-status=live |archive-url=https://web.archive.org/web/20150905085907/http://www.drugs.com/monograph/clonazepam.html |archive-date=5 September 2015 }}</ref> It is a long-acting<ref>{{cite book | vauthors = Basit H, Kahwaji CI | chapter = Clonazepam |date=2024 | title = StatPearls | chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK556010/ |access-date=2024-03-15 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=32310470 }}</ref> [[tranquilizer]] of the [[benzodiazepine]] class.<ref name="AHFS2015" /> It possesses [[anxiolytic]], [[anticonvulsant]], [[sedative]], [[hypnotic]], and [[skeletal muscle relaxant]] properties. It is typically taken [[oral administration|orally]] (swallowed by mouth) but is also used [[intravenously]].<ref name="AHFS2015" /><ref>{{cite journal | vauthors = Koubeissi M | title = Intravenous Clonazepam in Status Epilepticus | journal = Epilepsy Currents | volume = 16 | issue = 2 | pages = 89–90 | date = 2016 | pmid = 27073337 | pmc = 4822737 | doi = 10.5698/1535-7511-16.2.89 }}</ref> Effects begin within one hour and last between eight and twelve hours in adults.<ref name="Coop2007">{{cite book| veditors = Cooper G |title=Therapeutic uses of botulinum toxin|date=2007|publisher=Humana Press|location=Totowa, N.J.|isbn=9781597452472|page=214|url=https://books.google.com/books?id=UIUhCmMtqq8C&pg=PA214|url-status=live|archive-url=https://web.archive.org/web/20160819100221/https://books.google.ca/books?id=UIUhCmMtqq8C&pg=PA214|archive-date=19 August 2016}}</ref><ref name="Paxam_Data_Sheet">{{Cite web |title=Paxam Data Sheet |date=October 18, 2023 |url=https://www.medsafe.govt.nz/profs/datasheet/p/Paxamtab.pdf |access-date=March 14, 2024 |website=medsafe.govt.nz |archive-date=9 December 2023 |archive-url=https://web.archive.org/web/20231209033635/https://www.medsafe.govt.nz/profs/datasheet/p/Paxamtab.pdf |url-status=live }}</ref>

<!-- Side effects and mechanism -->

Common side effects may include sleepiness, poor coordination, and agitation.<ref name=AHFS2015/> [[Effects of long-term benzodiazepine use|Long-term use]] may result in [[Drug tolerance|tolerance]], [[benzodiazepine dependence|dependence]], and life-threatening [[benzodiazepine withdrawal syndrome|withdrawal symptoms]] if stopped abruptly.<ref name=AHFS2015/><ref>{{cite journal | vauthors = Edinoff AN, Nix CA, Hollier J, Sagrera CE, Delacroix BM, Abubakar T, Cornett EM, Kaye AM, Kaye AD | title = Benzodiazepines: Uses, Dangers, and Clinical Considerations | journal = Neurology International | volume = 13 | issue = 4 | pages = 594–607 | date = November 2021 | pmid = 34842811 | pmc = 8629021 | doi = 10.3390/neurolint13040059 | doi-access = free }}</ref> Dependence occurs in one-third of people who take benzodiazepines for longer than four weeks.<ref name="Riss-2008"/> The risk of [[suicide]] increases, particularly in people who are already depressed.<ref name=AHFS2015/><ref name=Dodd2017/> Use during pregnancy may result in harm to the fetus.<ref name=AHFS2015/> Clonazepam binds to [[GABAA receptor|GABA_A receptors]], thus increasing the effect of the chief [[Inhibitory postsynaptic potential|inhibitory]] [[neurotransmitter]] [[gamma-Aminobutyric acid|γ-aminobutyric acid]] (GABA).<ref name="Riss-2008">{{cite journal | vauthors = Riss J, Cloyd J, Gates J, Collins S | title = Benzodiazepines in epilepsy: pharmacology and pharmacokinetics | journal = Acta Neurologica Scandinavica | volume = 118 | issue = 2 | pages = 69–86 | date = August 2008 | pmid = 18384456 | doi = 10.1111/j.1600-0404.2008.01004.x | s2cid = 24453988 | doi-access = }}{{cbignore|bot=medic}}</ref>

<!-- History, society, and culture -->

Clonazepam was patented in 1960 and went on sale in 1975 in the United States from [[Hoffmann-La Roche|Roche]].<ref name=Fis2006>{{cite book |vauthors=Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=535 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA535 |access-date=28 July 2020 |archive-date=14 January 2023 |archive-url=https://web.archive.org/web/20230114172419/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA535 |url-status=live }}</ref><ref>{{cite book| vauthors = Shorter E |title=A Historical Dictionary of Psychiatry|date=2005|publisher=Oxford University Press|isbn=9780190292010|chapter-url=https://books.google.com/books?id=juAJCAAAQBAJ&pg=PT66|chapter=B|url-status=live|archive-url=https://web.archive.org/web/20151002125926/https://books.google.ca/books?id=juAJCAAAQBAJ&pg=PT66|archive-date=2 October 2015}}</ref> It is available as a [[Generic drug|generic medication]].<ref name=AHFS2015/> In 2021, it was the 46th-most commonly prescribed medication in the United States, with more than 14{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title=Clonazepam - Drug Usage Statistics | website=ClinCalc | url=https://clincalc.com/DrugStats/Drugs/Clonazepam | access-date=14 January 2024 | archive-date=29 April 2017 | archive-url=https://web.archive.org/web/20170429114759/https://clincalc.com/DrugStats/Drugs/Clonazepam | url-status=live }}</ref> In many areas of the world, it is commonly used as a [[Recreational drug use|recreational drug]].<ref>{{cite book| veditors = Martino D, Cavanna AE |title=Advances in the neurochemistry and neuropharmacology of Tourette Syndrome|date=2013|publisher=Elsevier Science |location=Burlington |isbn=9780124115613 |page=357 |url= https://books.google.com/books?id=RYhqAAAAQBAJ&pg=PA357|quote=In several countries, prescription and use is now severely limited due to abusive recreational use of clonazepam.|url-status=live|archive-url=https://web.archive.org/web/20151002132021/https://books.google.ca/books?id=RYhqAAAAQBAJ&pg=PA357|archive-date=2 October 2015}}</ref><ref>{{cite book | vauthors = Fisher GL |title=Encyclopedia of substance abuse prevention, treatment, & recovery |date=2009 |publisher=SAGE |location=Los Angeles |isbn=9781412950848|page=100|url=https://books.google.com/books?id=CGxXIspuXVMC&pg=PT134|quote=frequently abused|url-status=live|archive-url=https://web.archive.org/web/20160812092733/https://books.google.ca/books?id=CGxXIspuXVMC&pg=PT134|archive-date=12 August 2016}}</ref>

Clonazepam is prescribed for short-term management of [[epilepsy]], [[anxiety]], OCD and [[panic disorder]] with or without [[agoraphobia]].<ref>{{cite journal | vauthors = Rossetti AO, Reichhart MD, Schaller MD, Despland PA, Bogousslavsky J | title = Propofol treatment of refractory status epilepticus: a study of 31 episodes | journal = Epilepsia | volume = 45 | issue = 7 | pages = 757–763 | date = July 2004 | pmid = 15230698 | doi = 10.1111/j.0013-9580.2004.01904.x | s2cid = 350479 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ståhl Y, Persson A, Petters I, Rane A, Theorell K, Walson P | title = Kinetics of clonazepam in relation to electroencephalographic and clinical effects | journal = Epilepsia | volume = 24 | issue = 2 | pages = 225–231 | date = April 1983 | pmid = 6403345 | doi = 10.1111/j.1528-1157.1983.tb04883.x | s2cid = 2017627 }}</ref><ref>{{Cite web|url=https://www.nhs.uk/medicines/clonazepam/|title=Clonazepam: medicine to control seizures or fits, muscle spasms and restless legs syndrome|date=6 January 2020|website=nhs.uk|language=en|access-date=19 April 2020|archive-date=28 July 2020|archive-url=https://web.archive.org/web/20200728170146/https://www.nhs.uk/medicines/clonazepam/|url-status=live}}</ref>

===Seizures===

Clonazepam, like other benzodiazepines, while being a first-line treatment for acute seizures, is not suitable for the long-term treatment of seizures due to the development of tolerance to the anticonvulsant effects.

Clonazepam has been found effective in treating epilepsy in children, and the inhibition of seizure activity seemed to be achieved at low plasma levels of clonazepam.<ref name="pmid 12657420">{{cite journal | vauthors = Dahlin MG, Amark PE, Nergårdh AR | title = Reduction of seizures with low-dose clonazepam in children with epilepsy | journal = Pediatric Neurology | volume = 28 | issue = 1 | pages = 48–52 | date = January 2003 | pmid = 12657420 | doi = 10.1016/S0887-8994(02)00468-X }}</ref> As a result, clonazepam is sometimes used for certain rare childhood epilepsies, but it has been found to be ineffective in the control of infantile spasms.<ref>{{cite journal | vauthors = Hrachovy RA, Frost JD, Kellaway P, Zion TE | title = Double-blind study of ACTH vs prednisone therapy in infantile spasms | journal = The Journal of Pediatrics | volume = 103 | issue = 4 | pages = 641–645 | date = October 1983 | pmid = 6312008 | doi = 10.1016/S0022-3476(83)80606-4 }}</ref> Clonazepam is mainly prescribed for the acute management of epilepsies. Clonazepam has been found to be effective in the acute control of nonconvulsive [[status epilepticus]]; the benefits, though, tended to be transient in many people, and the addition of [[phenytoin]] for lasting control was required in these patients.<ref>{{cite journal | vauthors = Tomson T, Svanborg E, Wedlund JE | title = Nonconvulsive status epilepticus: high incidence of complex partial status | journal = Epilepsia | volume = 27 | issue = 3 | pages = 276–285 | date = May–Jun 1986 | pmid = 3698940 | doi = 10.1111/j.1528-1157.1986.tb03540.x | s2cid = 26694857 }}</ref>

It is also approved for treatment of typical and atypical absences (seizures), infantile [[Myoclonus|myoclonic]], myoclonic, and [[Atonic seizure|akinetic seizure]]s.<ref name="Clonazepam. A review of a new antic">{{cite journal | vauthors = Browne TR | title = Clonazepam. A review of a new anticonvulsant drug | journal = Archives of Neurology | volume = 33 | issue = 5 | pages = 326–332 | date = May 1976 | pmid = 817697 | doi = 10.1001/archneur.1976.00500050012003 }}</ref> A subgroup of people with [[Management of drug-resistant epilepsy|treatment resistant epilepsy]] may benefit from long-term use of clonazepam; the benzodiazepine [[clorazepate]] may be an alternative due to its slow onset of tolerance.<ref name="Riss-2008"/><ref>{{cite journal | vauthors = Song L, Liu F, Liu Y, Zhang R, Ji H, Jia Y | title = Clonazepam add-on therapy for drug-resistant epilepsy | journal = The Cochrane Database of Systematic Reviews | volume = 4 | issue = 4 | pages = CD012253 | date = April 2020 | pmid = 32309880 | pmc = 7168574 | doi = 10.1002/14651858.CD012253.pub3 }}</ref>

===Anxiety disorders===

* [[Panic disorder]] may occur with or without [[agoraphobia]].<ref>{{cite journal | vauthors = Cloos JM | title = The treatment of panic disorder | journal = Current Opinion in Psychiatry | volume = 18 | issue = 1 | pages = 45–50 | date = January 2005 | pmid = 16639183 | url = http://www.medscape.com/viewarticle/497207 | access-date = 25 September 2007 | url-status = live | archive-url = https://web.archive.org/web/20110404150908/http://www.medscape.com/viewarticle/497207 | archive-date = 4 April 2011 }}</ref>

* Clonazepam has also been found effective in treating other [[anxiety disorder]]s, such as [[Social anxiety disorder|social phobia]], but this is an [[off-label use]].<ref>{{cite journal | vauthors = Davidson JR, Potts N, Richichi E, Krishnan R, Ford SM, Smith R, Wilson WH | title = Treatment of social phobia with clonazepam and placebo | journal = Journal of Clinical Psychopharmacology | volume = 13 | issue = 6 | pages = 423–428 | date = December 1993 | pmid = 8120156 | doi = 10.1097/00004714-199312000-00008 }}</ref><ref>{{Cite book| vauthors = de Leon J |url=https://books.google.com/books?id=_LOzIqD3_NoC&q=Clonazepam+panic+approved&pg=PA56 |title=A Practitioner's Guide to Prescribing Antiepileptics and Mood Stabilizers for Adults with Intellectual Disabilities|date=2 March 2012|publisher=Springer Science & Business Media|isbn=978-1-4614-2012-5|language=en}}</ref>

The effectiveness of clonazepam in the short-term treatment of panic disorder has been demonstrated in [[Clinical trial|controlled clinical trials]]. Some long-term trials have suggested a benefit of clonazepam for up to three years without the development of [[drug tolerance|tolerance]].<ref>{{cite journal | vauthors = Nardi AE, Freire RC, Mochcovitch MD, Amrein R, Levitan MN, King AL, Valença AM, Veras AB, Paes F, Sardinha A, Nascimento I, de-Melo-Neto VL, Dias GP, E Silva AC, Soares-Filho GL, da Costa RT, Mezzasalma MA, de Carvalho MR, de Cerqueira AC, Hallak JE, Crippa JA, Versiani M | title = A randomized, naturalistic, parallel-group study for the long-term treatment of panic disorder with clonazepam or paroxetine | journal = Journal of Clinical Psychopharmacology | volume = 32 | issue = 1 | pages = 120–126 | date = February 2012 | pmid = 22198456 | doi = 10.1097/JCP.0b013e31823fe4bd | s2cid = 801184 }}</ref> Clonazepam is also effective in the management of [[Bipolar disorder|acute mania]].<ref>{{cite journal | vauthors = Nardi AE, Perna G | title = Clonazepam in the treatment of psychiatric disorders: an update | journal = International Clinical Psychopharmacology | volume = 21 | issue = 3 | pages = 131–142 | date = May 2006 | pmid = 16528135 | doi = 10.1097/01.yic.0000194379.65460.a6 | s2cid = 29469943 }}</ref>

===Muscle disorders===

[[Restless legs syndrome]] can be treated using clonazepam as a third-line treatment option, as the use of clonazepam is still investigational.<ref>{{cite journal | vauthors = | title = [Restless legs syndrome: diagnosis and treatment. Opinion of Brazilian experts] | language = Portuguese | journal = Arquivos de Neuro-Psiquiatria | volume = 65 | issue = 3A | pages = 721–727 | date = September 2007 | pmid = 17876423 | doi = 10.1590/S0004-282X2007000400035 | trans-title = Restless legs syndrome: diagnosis and treatment. Opinion of Brazilian experts | doi-access = free | hdl = 11449/69841 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Trenkwalder C, Hening WA, Montagna P, Oertel WH, Allen RP, Walters AS, Costa J, Stiasny-Kolster K, Sampaio C | title = Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice | journal = Movement Disorders | volume = 23 | issue = 16 | pages = 2267–2302 | date = December 2008 | pmid = 18925578 | doi = 10.1002/mds.22254 | url = http://www.movementdisorders.org/publications/ebm_reviews/treatmentofrls.pdf | url-status = dead | access-date = 19 January 2010 | s2cid = 91440 | archive-url = https://web.archive.org/web/20091229102940/http://www.movementdisorders.org/publications/ebm_reviews/treatmentofrls.pdf | archive-date = 29 December 2009 }}</ref> [[Bruxism]] also responds to clonazepam in the short term.<ref name="Huynh-">{{cite journal | vauthors = Huynh NT, Rompré PH, Montplaisir JY, Manzini C, Okura K, Lavigne GJ | title = Comparison of various treatments for sleep bruxism using determinants of number needed to treat and effect size | journal = The International Journal of Prosthodontics | volume = 19 | issue = 5 | pages = 435–441 | year = 2006 | pmid = 17323720 }}</ref> [[Rapid eye movement sleep behavior disorder|REM sleep behavior disorder]] responds well to low doses of clonazepam.<ref name="Ferini-Strambi">{{cite journal | vauthors = Ferini-Strambi L, Zucconi M | title = REM sleep behavior disorder | journal = Clinical Neurophysiology | volume = 111 | issue = Suppl 2 | pages = S136–S140 | date = September 2000 | pmid = 10996567 | doi = 10.1016/S1388-2457(00)00414-4 | s2cid = 43692512 }}</ref> It is also used for:

* The treatment of acute and chronic [[akathisia]] induced by [[Antipsychotic|neuroleptics]], also called [[antipsychotic]]s<ref>{{cite journal | vauthors = Nelson DE | title = Akathisia--a brief review | journal = Scottish Medical Journal | volume = 46 | issue = 5 | pages = 133–134 | date = October 2001 | pmid = 11771491 | doi = 10.1177/003693300104600502 | url = http://smj.org.uk/1001/aka1001.htm | url-status = dead | access-date = 1 March 2009 | s2cid = 45721265 | archive-url = https://web.archive.org/web/20090323083647/http://smj.org.uk/1001/aka1001.htm | archive-date = 23 March 2009 | url-access = subscription }}</ref><ref>{{cite journal | vauthors = Horiguchi J, Nishimatsu O, Inami Y | title = Successful treatment with clonazepam for neuroleptic-induced akathisia | journal = Acta Psychiatrica Scandinavica | volume = 80 | issue = 1 | pages = 106–107 | date = July 1989 | pmid = 2569804 | doi = 10.1111/j.1600-0447.1989.tb01308.x | s2cid = 27621771 }}</ref>

* [[Spasticity]] related to [[amyotrophic lateral sclerosis]]<ref>{{cite journal | vauthors = Lipton SA, Rosenberg PA | title = Excitatory amino acids as a final common pathway for neurologic disorders | journal = The New England Journal of Medicine | volume = 330 | issue = 9 | pages = 613–622 | date = March 1994 | pmid = 7905600 | doi = 10.1056/NEJM199403033300907 }}</ref>

===Other===

* Benzodiazepines, such as clonazepam, are sometimes used for the treatment of [[mania]] or acute [[psychosis]]-induced aggression. In this context, benzodiazepines are given either alone or in combination with other first-line drugs such as [[Lithium pharmacology|lithium]], [[haloperidol]], or [[risperidone]].<ref>{{cite journal | vauthors = Curtin F, Schulz P | title = Clonazepam and lorazepam in acute mania: a Bayesian meta-analysis | journal = Journal of Affective Disorders | volume = 78 | issue = 3 | pages = 201–208 | date = March 2004 | pmid = 15013244 | doi = 10.1016/S0165-0327(02)00317-8 }}</ref><ref name=":Gillies2013">{{cite journal | vauthors = Gillies D, Sampson S, Beck A, Rathbone J | title = Benzodiazepines for psychosis-induced aggression or agitation | journal = The Cochrane Database of Systematic Reviews | volume = 4 | issue = 4 | pages = CD003079 | date = April 2013 | pmid = 23633309 | doi = 10.1002/14651858.CD003079.pub3 | hdl-access = free | hdl = 10454/16512 }}</ref> The effectiveness of taking benzodiazepines along with [[Antipsychotic|antipsychotic medication]] is unknown, and more research is needed to determine if benzodiazepines are more effective than antipsychotics when urgent sedation is required.<ref name=":Gillies2013" />

* [[Hyperekplexia]]<ref>{{cite journal | vauthors = Zhou L, Chillag KL, Nigro MA | title = Hyperekplexia: a treatable neurogenetic disease | journal = Brain & Development | volume = 24 | issue = 7 | pages = 669–674 | date = October 2002 | pmid = 12427512 | doi = 10.1016/S0387-7604(02)00095-5 | s2cid = 40864297 }}</ref>

* Many forms of [[parasomnia]] and other sleep disorders are treated with clonazepam.<ref>{{cite journal | vauthors = Schenck CH, Arnulf I, Mahowald MW | title = Sleep and sex: what can go wrong? A review of the literature on sleep related disorders and abnormal sexual behaviors and experiences | journal = Sleep | volume = 30 | issue = 6 | pages = 683–702 | date = June 2007 | pmid = 17580590 | pmc = 1978350 | doi = 10.1093/sleep/30.6.683 }}</ref>

* It is not effective for preventing [[migraine]]s.<ref>{{cite journal | vauthors = Mulleners WM, Chronicle EP | title = Anticonvulsants in migraine prophylaxis: a Cochrane review | journal = Cephalalgia | volume = 28 | issue = 6 | pages = 585–597 | date = June 2008 | pmid = 18454787 | doi = 10.1111/j.1468-2982.2008.01571.x | s2cid = 24233098 | doi-access = free }}</ref>

== Contraindications ==

* Coma

* Current [[alcohol use disorder]]

* Current substance use disorder

* [[Respiratory depression]]<ref>{{cite web | author = Joint Formulary Committee | title = British National Formulary (online) | location = London | publisher = BMJ Group and Pharmaceutical Press | url = http://www.medicinescomplete.com/ | access-date = 2 February 2020 | archive-date = 10 June 2021 | archive-url = https://web.archive.org/web/20210610002537/https://www.medicinescomplete.com/ | url-status = live }}</ref>

==Adverse effects==

In September 2020, the U.S. [[Food and Drug Administration]] <!-- (FDA) --> required the [[boxed warning]] 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. [[Food and Drug Administration]] (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 | archive-date=24 September 2020 | archive-url=https://web.archive.org/web/20200924002523/https://www.fda.gov/drugs/drug-safety-and-availability/fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class | url-status=live }} {{PD-notice}}</ref>

===Common===

* [[Sedation]]<ref>{{cite journal | vauthors = Stacy M | title = Sleep disorders in Parkinson's disease: epidemiology and management | journal = Drugs & Aging | volume = 19 | issue = 10 | pages = 733–739 | year = 2002 | pmid = 12390050 | doi = 10.2165/00002512-200219100-00002 | s2cid = 40376995 }}</ref>

* [[Psychomotor retardation|Motor impairment]]

* [[Confusion]]<ref name="Riss-2008"/>

* Irritability and aggression<ref>{{cite journal | vauthors = Lander CM, Donnan GA, Bladin PF, Vajda FJ | title = Some aspects of the clinical use of clonazepam in refractory epilepsy | journal = Clinical and Experimental Neurology | volume = 16 | pages = 325–332 | year = 1979 | pmid = 121707 }}</ref>

* [[Psychomotor agitation]]<ref>{{cite journal | vauthors = Sorel L, Mechler L, Harmant J | title = Comparative trial of intravenous lorazepam and clonazepam im status epilepticus | journal = Clinical Therapeutics | volume = 4 | issue = 4 | pages = 326–336 | year = 1981 | pmid = 6120763 }}</ref>

* Lack of motivation<ref>{{cite journal | vauthors = Wollman M, Lavie P, Peled R | title = A hypernychthemeral sleep-wake syndrome: a treatment attempt | journal = Chronobiology International | volume = 2 | issue = 4 | pages = 277–280 | year = 1985 | pmid = 3870855 | doi = 10.3109/07420528509055890 }}</ref>

* Impaired motor function<!-- {{Vague|date=February 2014}} -->

* Cognitive impairments{{Vague|date=February 2014}}<ref name="meylers_side_effects_of_psychiatric_drugs">{{Cite book | vauthors = Aronson JK | title = Meyler's Side Effects of Psychiatric Drugs (Meylers Side Effects) | date = 20 November 2008 | publisher = Elsevier Science | isbn = 978-0-444-53266-4 | page = 403 }}</ref>

** [[Hallucination]]s.<ref>{{cite web |url=https://www.drugs.com/sfx/clonazepam-side-effects.html |title=Clonazepam Side Effects |year=2010 |publisher=Drugs.com |url-status=live |archive-url=https://web.archive.org/web/20100428055102/http://www.drugs.com/sfx/clonazepam-side-effects.html |archive-date=28 April 2010 }}</ref>

** Short-term memory loss<ref name="the_interface_of_neurology_internal_medicine">{{Cite book | title = The interface of neurology internal medicine | date = 1 September 2007 | url = https://books.google.com/books?id=SRIvmTVcYBwC&pg=RA2-PA963| publisher = Wolters Kluwer Health/Lippincott Williams Wilkins | location = Philadelphia | isbn = 978-0-7817-7906-7 | pages = 963 }}</ref>

** [[Anterograde amnesia]] (common with higher doses)<ref name="the_american_psychiatric_publishing_textbook_of_psychoph_a01">{{Cite book | title = The American Psychiatric Publishing Textbook of Psychopharmacology (Schatzberg, American Psychiatric Publishing Textbook of Psychopharmacology) | url = https://books.google.com/books?id=Xx7iNGdV25IC&pg=PA471 | date = 31 July 2009 | publisher = American Psychiatric Publishing, Inc. | location = USA | isbn = 978-1-58562-309-9 | page = 471 }}</ref>

* Some users report [[hangover]]-like symptoms of drowsiness, headaches, sluggishness, and irritability upon waking up if the medication was taken before sleep. This is likely the result of the medication's long half-life, which continues to affect the user after waking up.<ref>{{Cite web|url=http://thechart.blogs.cnn.com/2011/06/07/beware-the-sleeping-pill-hangover/|title=Get Some Sleep: Beware the sleeping pill hangover|access-date=21 June 2017|url-status=live|archive-url=https://web.archive.org/web/20170721005429/http://thechart.blogs.cnn.com/2011/06/07/beware-the-sleeping-pill-hangover/|archive-date=21 July 2017}}</ref><ref name="narcolepsy_a05">{{Cite book | vauthors = Goswami M, Pandi-Perumal SR, Thorpy MJ | title = Narcolepsy:: A Clinical Guide | url = https://books.google.com/books?id=GvlZRKF_IA8C&pg=PA73 | date = 24 March 2010 | publisher = Springer | isbn = 978-1-4419-0853-7 | page = 73 }}</ref><ref name="principles_of_psychopharmacology_for_mental_health_profession">{{Cite book | vauthors = Kelsey JE, Newport DJ, Nemeroff CB | title = Principles of psychopharmacology for mental health professionals | year = 2006 | publisher = Wiley-Liss | location = Hoboken, N.J. | url = https://books.google.com/books?id=FxaBz-ufvN0C&pg=PA269 | isbn = 978-0-471-25401-0 | page = 269 }}</ref> While benzodiazepines induce sleep, they tend to reduce the quality of sleep by suppressing or disrupting REM sleep.<ref name="sleep_medicine_a04">{{Cite book | vauthors = Lee-chiong T | title = Sleep Medicine: Essentials and Review | url = https://books.google.com/books?id=2gzxPOBzZgUC&pg=PA463 | date = 24 April 2008 | publisher = Oxford University Press, USA | isbn = 978-0-19-530659-0 | pages = 463–465 }}</ref> After regular use, [[rebound insomnia]] may occur when discontinuing clonazepam.<ref name="katzung_trevors_review_of_pharmacology">{{Cite book | vauthors = Trevor AJ, Katzung BG, Masters SB | title = Katzung Trevor's pharmacology: examination board review | url = https://books.google.com/books?id=Bvtkl3XUC5AC&pg=PA191 | date = 1 January 2008 | publisher = McGraw Hill Medical | location = New York | isbn = 978-0-07-148869-3 | page = 191 | access-date = 28 July 2020 | archive-date = 14 January 2023 | archive-url = https://web.archive.org/web/20230114180644/https://books.google.com/books?id=Bvtkl3XUC5AC&pg=PA191 | url-status = live }}</ref>

* Benzodiazepines may cause or worsen [[Major depressive disorder|depression]].<ref name="Riss-2008"/>

* [[Dysphoria]]<ref>{{cite journal | vauthors = Sjö O, Hvidberg EF, Naestoft J, Lund M | title = Pharmacokinetics and side-effects of clonazepam and its 7-amino-metabolite in man | journal = European Journal of Clinical Pharmacology | volume = 8 | issue = 3–4 | pages = 249–254 | date = April 1975 | pmid = 1233220 | doi = 10.1007/BF00567123 | s2cid = 27095161 }}</ref>

* Induction of seizures<ref>{{cite journal | vauthors = Alvarez N, Hartford E, Doubt C | title = Epileptic seizures induced by clonazepam | journal = Clinical EEG | volume = 12 | issue = 2 | pages = 57–65 | date = April 1981 | pmid = 7237847 | doi = 10.1177/155005948101200203 | s2cid = 39403793 }}</ref><ref>{{cite journal | vauthors = Ishizu T, Chikazawa S, Ikeda T, Suenaga E | title = [Multiple types of seizure induced by clonazepam in an epileptic patient] | language = ja | journal = No to Hattatsu = Brain and Development | volume = 20 | issue = 4 | pages = 337–339 | date = July 1988 | pmid = 3214607 }}</ref> or increased frequency of seizures<ref>{{cite journal | vauthors = Bang F, Birket-Smith E, Mikkelsen B | title = Clonazepam in the treatment of epilepsy. A clinical long-term follow-up study | journal = Epilepsia | volume = 17 | issue = 3 | pages = 321–324 | date = September 1976 | pmid = 824124 | doi = 10.1111/j.1528-1157.1976.tb03410.x | s2cid = 31409580 }}</ref>

* Personality changes<ref name="clonepi">{{cite journal | vauthors = Bruni J | title = Recent advances in drug therapy for epilepsy | journal = Canadian Medical Association Journal | volume = 120 | issue = 7 | pages = 817–824 | date = April 1979 | pmid = 371777 | pmc = 1818965 | type = PDF }}</ref>

* Behavioural disturbances<ref>{{cite journal | vauthors = Rosenfeld WE, Beniak TE, Lippmann SM, Loewenson RB | title = Adverse behavioral response to clonazepam as a function of Verbal IQ-Performance IQ discrepancy | journal = Epilepsy Research | volume = 1 | issue = 6 | pages = 347–356 | year = 1987 | pmid = 3504409 | doi = 10.1016/0920-1211(87)90059-3 | s2cid = 40893264 }}</ref>

* Suicide through disinhibition<ref name=Dodd2017>{{cite journal | vauthors = Dodds TJ | title = Prescribed Benzodiazepines and Suicide Risk: A Review of the Literature | journal = The Primary Care Companion for CNS Disorders | volume = 19 | issue = 2 | date = March 2017 | pmid = 28257172 | doi = 10.4088/PCC.16r02037 | doi-access = free }}</ref>

* [[Psychosis]]<ref>{{cite journal | vauthors = White MC, Silverman JJ, Harbison JW | title = Psychosis associated with clonazepam therapy for blepharospasm | journal = The Journal of Nervous and Mental Disease | volume = 170 | issue = 2 | pages = 117–119 | date = February 1982 | pmid = 7057171 | doi = 10.1097/00005053-198202000-00010 }}</ref>

* [[Urinary incontinence|Incontinence]]<ref>{{cite journal | vauthors = Williams A, Gillespie M | title = Clonazepam-induced incontinence | journal = Annals of Neurology | volume = 6 | issue = 1 | pages = 86 | date = July 1979 | pmid = 507767 | doi = 10.1002/ana.410060127 | s2cid = 36023934 }}</ref><ref>{{cite journal | vauthors = Sandyk R | title = Urinary incontinence associated with clonazepam therapy | journal = South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde | volume = 64 | issue = 7 | pages = 230 | date = August 1983 | pmid = 6879368 }}</ref><ref>{{cite journal | vauthors = Anders RJ, Wang E, Radhakrishnan J, Sharifi R, Lee M | title = Overflow urinary incontinence due to carbamazepine | journal = The Journal of Urology | volume = 134 | issue = 4 | pages = 758–759 | date = October 1985 | pmid = 4032590 | doi = 10.1016/S0022-5347(17)47428-3 }}</ref>

* Paradoxical behavioural disinhibition<ref name="Riss-2008"/><ref name="pmid2019899">{{cite journal | vauthors = van der Bijl P, Roelofse JA | title = Disinhibitory reactions to benzodiazepines: a review | journal = Journal of Oral and Maxillofacial Surgery | volume = 49 | issue = 5 | pages = 519–523 | date = May 1991 | pmid = 2019899 | doi = 10.1016/0278-2391(91)90180-T | doi-access = free }}</ref> (most frequently in children, the elderly, and in persons with developmental disabilities)

The [[Long-term effects of benzodiazepines|long-term effects of clonazepam]] can include depression,<ref name="Riss-2008"/> [[disinhibition]], and [[sexual dysfunction]].<ref>{{cite journal | vauthors = Cohen LS, Rosenbaum JF | title = Clonazepam: new uses and potential problems | journal = The Journal of Clinical Psychiatry | volume = 48 | issue = Suppl | pages = 50–56 | date = October 1987 | pmid = 2889724 }}</ref>

===Drowsiness===

Clonazepam, like other benzodiazepines, may impair a person's ability to drive or operate machinery. The central nervous system depressing effects of the drug can be intensified by [[alcohol (drug)|alcohol]] consumption, so alcohol should be avoided while taking this medication. Benzodiazepines have been shown to cause dependence. Patients dependent on clonazepam should be slowly titrated off under the supervision of a qualified healthcare professional to reduce the intensity of withdrawal or rebound symptoms.

* Anxiety

* Irritability

* Insomnia

* Tremors

* Headaches

* Stomach pain

* Hallucinations

* Suicidal thoughts or urges

* Depression

* Fatigue

* Dizziness

* Sweating

* Confusion

* Potential to exacerbate existing panic disorder upon discontinuation

* Seizures<ref>{{cite journal | vauthors = Lockard JS, Levy RH, Congdon WC, DuCharme LL, Salonen LD | title = Clonazepam in a focal-motor monkey model: efficacy, tolerance, toxicity, withdrawal, and management | journal = Epilepsia | volume = 20 | issue = 6 | pages = 683–695 | date = December 1979 | pmid = 115680 | doi = 10.1111/j.1528-1157.1979.tb04852.x | s2cid = 31346286 }}</ref> similar to [[delirium tremens]] (with long-term use of excessive doses)

Benzodiazepines such as clonazepam can be very effective in controlling [[status epilepticus]], but, when used for longer periods of time, some potentially serious side-effects may develop, such as interference with [[Cognition|cognitive]] functions and behavior.<ref>{{cite journal | vauthors = Vining EP | title = Use of barbiturates and benzodiazepines in treatment of epilepsy | journal = Neurologic Clinics | volume = 4 | issue = 3 | pages = 617–632 | date = August 1986 | pmid = 3528811 | doi = 10.1016/S0733-8619(18)30966-6 }}</ref> Many individuals treated on a long-term basis develop a dependence. [[Physiology|Physiological]] dependence was demonstrated by [[flumazenil]]-precipitated withdrawal.<ref>{{cite journal | vauthors = Bernik MA, Gorenstein C, Vieira Filho AH | title = Stressful reactions and panic attacks induced by flumazenil in chronic benzodiazepine users | journal = Journal of Psychopharmacology | volume = 12 | issue = 2 | pages = 146–150 | year = 1998 | pmid = 9694026 | doi = 10.1177/026988119801200205 | s2cid = 24348950 }}</ref> Use of alcohol or other [[Central nervous system|CNS]] depressants while taking clonazepam greatly intensifies the effects, including side effects, of the drug.

A recurrence of symptoms of the underlying disease should be separated from withdrawal symptoms.<ref>{{cite book | vauthors = Stahl SM |date=2014 |title=Stahl's Essential Psychopharmacology: Prescriber's Guide |edition=5th |location=San Diego, CA |publisher=Cambridge University Press |page=139 |isbn=978-1-107-67502-5 |url=https://books.google.com/books?id=Q7hkAwAAQBAJ&pg=PA139 }}</ref>

===Tolerance and withdrawal===

Like all benzodiazepines, clonazepam is a GABA-positive [[allosteric modulator]].<ref>{{cite journal | vauthors = Adjeroud S, Tonon MC, Leneveu E, Lamacz M, Danger JM, Gouteux L, Cazin L, Vaudry H | title = The benzodiazepine agonist clonazepam potentiates the effects of gamma-aminobutyric acid on alpha-MSH release from neurointermediate lobes in vitro | journal = Life Sciences | volume = 40 | issue = 19 | pages = 1881–1887 | date = May 1987 | pmid = 3033417 | doi = 10.1016/0024-3205(87)90046-4 }}</ref><ref>{{cite journal | vauthors = Yokota K, Tatebayashi H, Matsuo T, Shoge T, Motomura H, Matsuno T, Fukuda A, Tashiro N | title = The effects of neuroleptics on the GABA-induced Cl- current in rat dorsal root ganglion neurons: differences between some neuroleptics | journal = British Journal of Pharmacology | volume = 135 | issue = 6 | pages = 1547–1555 | date = March 2002 | pmid = 11906969 | pmc = 1573270 | doi = 10.1038/sj.bjp.0704608 }}</ref> One-third of individuals treated with benzodiazepines for longer than four weeks develop a dependence on the drug and experience a withdrawal syndrome upon dose reduction. High dosage and long-term use increase the risk and severity of dependence and withdrawal symptoms. Withdrawal seizures and psychosis can occur in severe cases of withdrawal, and anxiety and insomnia can occur in less severe cases of withdrawal. A gradual reduction in dosage reduces the severity of the [[benzodiazepine withdrawal syndrome]]. Due to the risks of tolerance and withdrawal seizures, clonazepam is generally not recommended for the long-term management of epilepsies. Increasing the dose can overcome the effects of tolerance, but tolerance to the higher dose may occur and adverse effects may intensify. The mechanism of tolerance includes receptor desensitization, down regulation, receptor decoupling, and alterations in subunit composition and in [[Transcription (biology)|gene transcription]] coding.<ref name="Riss-2008"/>

[[Drug tolerance|Tolerance]] to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently.<ref>{{cite journal | vauthors = Loiseau P | title = [Benzodiazepines in the treatment of epilepsy] | journal = L'Encephale | volume = 9 | issue = 4 Suppl 2 | pages = 287B–292B | year = 1983 | pmid = 6373234 }}</ref><ref>{{cite journal | vauthors = Scherkl R, Scheuler W, Frey HH | title = Anticonvulsant effect of clonazepam in the dog: development of tolerance and physical dependence | journal = Archives Internationales de Pharmacodynamie et de Therapie | volume = 278 | issue = 2 | pages = 249–260 | date = December 1985 | pmid = 4096613 }}</ref> Chronic use of benzodiazepines can lead to the development of tolerance with a decrease of benzodiazepine binding sites. The degree of tolerance is more pronounced with clonazepam than with [[chlordiazepoxide]].<ref>{{cite journal | vauthors = Crawley JN, Marangos PJ, Stivers J, Goodwin FK | title = Chronic clonazepam administration induces benzodiazepine receptor subsensitivity | journal = Neuropharmacology | volume = 21 | issue = 1 | pages = 85–89 | date = January 1982 | pmid = 6278355 | doi = 10.1016/0028-3908(82)90216-7 | s2cid = 24771398 | author-link = Jacqueline Crawley }}</ref> In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy.<ref>{{cite journal | vauthors = Bacia T, Purska-Rowińska E, Okuszko S | title = Clonazepam in the treatment of drug-resistant epilepsy: a clinical short and long term follow-up study | journal = Monographs in Neural Sciences | volume = 5 | pages = 153–159 | year = 1980 | pmid = 7033770 | doi = 10.1159/000387498 | isbn = 978-3-8055-0635-9 | series = Frontiers of Neurology and Neuroscience }}</ref> Many studies have found that tolerance develops to the anticonvulsant properties of clonazepam with chronic use, which limits its long-term effectiveness as an anticonvulsant.<ref name="Clonazepam. A review of a new antic"/>

Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndrome, causing psychosis characterised by [[Dysphoria|dysphoric]] manifestations, irritability, aggressiveness, anxiety, and hallucinations.<ref>{{cite journal | vauthors = Sironi VA, Miserocchi G, De Riu PL | title = Clonazepam withdrawal syndrome | journal = Acta Neurologica | volume = 6 | issue = 2 | pages = 134–139 | date = April 1984 | pmid = 6741654 }}</ref><ref>{{cite journal | vauthors = Sironi VA, Franzini A, Ravagnati L, Marossero F | title = Interictal acute psychoses in temporal lobe epilepsy during withdrawal of anticonvulsant therapy | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 42 | issue = 8 | pages = 724–730 | date = August 1979 | pmid = 490178 | pmc = 490305 | doi = 10.1136/jnnp.42.8.724 }}</ref><ref>{{cite journal | vauthors = Jaffe R, Gibson E | title = Clonazepam withdrawal psychosis | journal = Journal of Clinical Psychopharmacology | volume = 6 | issue = 3 | pages = 193 | date = June 1986 | pmid = 3711371 | doi = 10.1097/00004714-198606000-00021 }}</ref> Sudden withdrawal may also induce the potentially life-threatening condition, [[status epilepticus]]. Anti-epileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced in dose slowly and gradually when discontinuing the drug to mitigate withdrawal effects.<ref name="clonepi"/> [[Carbamazepine]] has been tested in the treatment of clonazepam withdrawal but was found to be ineffective in preventing clonazepam withdrawal-induced [[status epilepticus]] from occurring.<ref>{{cite journal | vauthors = Sechi GP, Zoroddu G, Rosati G | title = Failure of carbamazepine to prevent clonazepam withdrawal status epilepticus | journal = Italian Journal of Neurological Sciences | volume = 5 | issue = 3 | pages = 285–287 | date = September 1984 | pmid = 6500901 | doi = 10.1007/BF02043959 | s2cid = 23094043 }}</ref>

===Overdose===

{{Main|Benzodiazepine overdose}}

Excess doses may result in:

* [[Somnolence|Difficulty staying awake]]

* Mental confusion

* Impaired motor functions

** Impaired reflexes

** Impaired coordination

** Impaired balance

** Dizziness

* Respiratory depression

* [[Hypotension|Low blood pressure]]

* [[Coma]]

Coma can be cyclic, with the individual alternating from a comatose state to a hyper-alert state of consciousness, which occurred in a four-year-old boy who overdosed on clonazepam.<ref>{{cite journal | vauthors = Welch TR, Rumack BH, Hammond K | title = Clonazepam overdose resulting in cyclic coma | journal = Clinical Toxicology | volume = 10 | issue = 4 | pages = 433–436 | year = 1977 | pmid = 862377 | doi = 10.3109/15563657709046280 }}</ref> The combination of clonazepam and certain barbiturates (for example, [[amobarbital]]), at prescribed doses has resulted in a [[Synergy|synergistic]] potentiation of the effects of each drug, leading to serious respiratory depression.<ref>{{cite journal | vauthors = Honer WG, Rosenberg RG, Turey M, Fisher WA | title = Respiratory failure after clonazepam and amobarbital | journal = The American Journal of Psychiatry | volume = 143 | issue = 11 | pages = 1495b–1495 | date = November 1986 | pmid = 3777263 | doi = 10.1176/ajp.143.11.1495b }}</ref>

Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.<ref>{{cite web |url=http://drugsdb.eu/drug.php?d=Clonazepam&m=Contract%20Pharmacy%20Services-pa&id=52a03dbc-0510-40ec-8a33-15bf1c404622.xml |title=Clonazepam, Prescription Marketed Drugs |url-status=live |archive-url=https://web.archive.org/web/20120425025645/http://drugsdb.eu/drug.php?d=Clonazepam&m=Contract%20Pharmacy%20Services-pa&id=52a03dbc-0510-40ec-8a33-15bf1c404622.xml |archive-date=25 April 2012 }}</ref>

===Detection in biological fluids===

Clonazepam and 7-aminoclonazepam may be quantified in [[Blood plasma|plasma]], [[serum (blood)|serum]], or [[whole blood]] in order to monitor compliance in those receiving the drug therapeutically. Results from such tests can be used to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. Both the parent drug and 7-aminoclonazepam are unstable in biofluids, and therefore specimens should be preserved with sodium fluoride, stored at the lowest possible temperature and analyzed quickly to minimize losses.<ref>R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 335-337.</ref>

===Special precautions===

The elderly metabolize benzodiazepines more slowly than younger people and are also more sensitive to the effects of benzodiazepines, even at similar blood plasma levels. Doses for the elderly are recommended to be about half of that given to younger adults and are to be administered for no longer than two weeks. Long-acting benzodiazepines such as clonazepam are not generally recommended for the elderly due to the risk of drug accumulation.<ref name="Riss-2008"/>

The elderly are especially susceptible to increased risk of harm from motor impairments and drug accumulation side effects. Benzodiazepines also require special precaution if used by individuals that may be pregnant, alcohol- or drug-dependent, or may have [[Comorbidity|comorbid]] [[Mental disorder|psychiatric disorders]].<ref name="Authier-2009">{{cite journal | vauthors = Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, Vennat B, Llorca PM, Eschalier A | 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> Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.<ref>{{cite journal | vauthors = Wolkove N, Elkholy O, Baltzan M, Palayew M | title = Sleep and aging: 2. Management of sleep disorders in older people | journal = CMAJ | volume = 176 | issue = 10 | pages = 1449–1454 | date = May 2007 | pmid = 17485699 | pmc = 1863539 | doi = 10.1503/cmaj.070335 }}</ref>

Clonazepam is not recommended for use in those under 18. Use in very young children may be especially hazardous. Of anticonvulsant drugs, behavioural disturbances occur most frequently with clonazepam and [[phenobarbital]].<ref name="Authier-2009"/><ref>{{cite journal | vauthors = Trimble MR, Cull C | title = Children of school age: the influence of antiepileptic drugs on behavior and intellect | journal = Epilepsia | volume = 29 | issue = Suppl 3 | pages = S15–S19 | year = 1988 | pmid = 3066616 | doi = 10.1111/j.1528-1157.1988.tb05805.x | s2cid = 20440040 }}</ref>

Doses higher than 0.5–1&nbsp;mg per day are associated with significant sedation.<ref>{{cite journal | vauthors = Hollister LE | title = Dose-ranging studies of clonazepam in man | journal = Psychopharmacology Communications | volume = 1 | issue = 1 | pages = 89–92 | year = 1975 | pmid = 1223993 }}</ref>

Clonazepam may aggravate [[hepatic porphyria]].<ref name="Bonkowsky">{{cite journal | vauthors = Bonkowsky HL, Sinclair PR, Emery S, Sinclair JF | title = Seizure management in acute hepatic porphyria: risks of valproate and clonazepam | journal = Neurology | volume = 30 | issue = 6 | pages = 588–592 | date = June 1980 | pmid = 6770287 | doi = 10.1212/WNL.30.6.588 | s2cid = 21137619 }}</ref><ref>{{cite journal | vauthors = Reynolds NC, Miska RM | title = Safety of anticonvulsants in hepatic porphyrias | journal = Neurology | volume = 31 | issue = 4 | pages = 480–484 | date = April 1981 | pmid = 7194443 | doi = 10.1212/wnl.31.4.480 | s2cid = 40044726 }}</ref>

Clonazepam is not recommended for patients with chronic [[schizophrenia]]. A 1982 double-blinded, placebo-controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia.<ref>{{cite journal | vauthors = Karson CN, Weinberger DR, Bigelow L, Wyatt RJ | title = Clonazepam treatment of chronic schizophrenia: negative results in a double-blind, placebo-controlled trial | journal = The American Journal of Psychiatry | volume = 139 | issue = 12 | pages = 1627–1628 | date = December 1982 | pmid = 6756174 | doi = 10.1176/ajp.139.12.1627 }}</ref>

Clonazepam has similar effectiveness to other benzodiazepines at often a lower dose.<ref>{{cite web|title=Benzodiazepine Equivalency Table: Benzodiazepine Equivalency|url=https://emedicine.medscape.com/article/2172250-overview#a1|access-date=19 February 2018|date=28 April 2017|archive-date=2 November 2017|archive-url=https://web.archive.org/web/20171102050448/https://emedicine.medscape.com/article/2172250-overview#a1|url-status=live}}</ref>

== Interactions ==

Clonazepam decreases the levels of [[carbamazepine]],<ref name="pmid2912">{{cite journal | vauthors = Lander CM, Eadie MJ, Tyrer JH | title = Interactions between anticonvulsants | journal = Proceedings of the Australian Association of Neurologists | volume = 12 | pages = 111–116 | year = 1975 | pmid = 2912 }}</ref><ref>{{cite journal | vauthors = Pippenger CE | title = Clinically significant carbamazepine drug interactions: an overview | journal = Epilepsia | volume = 28 | issue = Suppl 3 | pages = S71–S76 | year = 1987 | pmid = 3319544 | doi = 10.1111/j.1528-1157.1987.tb05781.x | s2cid = 22680377 }}</ref> and, likewise, clonazepam's level is reduced by carbamazepine. Azole antifungals, such as [[ketoconazole]], may inhibit the metabolism of clonazepam.<ref name="Riss-2008"/> Clonazepam may affect levels of [[phenytoin]] (diphenylhydantoin).<ref name="pmid2912"/><ref>{{cite journal | vauthors = Saavedra IN, Aguilera LI, Faure E, Galdames DG | title = Phenytoin/clonazepam interaction | journal = Therapeutic Drug Monitoring | volume = 7 | issue = 4 | pages = 481–484 | date = August 1985 | pmid = 4082246 | doi = 10.1097/00007691-198512000-00022 }}</ref><ref name="inter">{{cite journal | vauthors = Windorfer A, Sauer W | title = Drug interactions during anticonvulsant therapy in childhood: diphenylhydantoin, primidone, phenobarbitone, clonazepam, nitrazepam, carbamazepin and dipropylacetate | journal = Neuropadiatrie | volume = 8 | issue = 1 | pages = 29–41 | date = February 1977 | pmid = 321985 | doi = 10.1055/s-0028-1091502 | s2cid = 9487285 }}</ref><ref>{{cite journal | vauthors = Windorfer A, Weinmann HM, Stünkel S | title = [Laboratory controls in long-term treatment with anticonvulsive drugs (author's transl)] | journal = Monatsschrift Fur Kinderheilkunde | volume = 125 | issue = 3 | pages = 122–128 | date = March 1977 | pmid = 323695 }}</ref> In turn, Phenytoin may lower clonazepam plasma levels by increasing the speed of clonazepam clearance by approximately 50% and decreasing its half-life by 31%.<ref>{{cite journal | vauthors = Khoo KC, Mendels J, Rothbart M, Garland WA, Colburn WA, Min BH, Lucek R, Carbone JJ, Boxenbaum HG, Kaplan SA | title = Influence of phenytoin and phenobarbital on the disposition of a single oral dose of clonazepam | journal = Clinical Pharmacology and Therapeutics | volume = 28 | issue = 3 | pages = 368–375 | date = September 1980 | pmid = 7408397 | doi = 10.1038/clpt.1980.175 | s2cid = 21980890 }}</ref>

Clonazepam increases the levels of [[primidone]]<ref name="inter"/> and [[phenobarbital]].<ref>{{cite journal | vauthors = Bendarzewska-Nawrocka B, Pietruszewska E, Stepień L, Bidziński J, Bacia T | title = [Relationship between blood serum luminal and diphenylhydantoin level and the results of treatment and other clinical data in drug-resistant epilepsy] | journal = Neurologia I Neurochirurgia Polska | volume = 14 | issue = 1 | pages = 39–45 | year = 1980 | pmid = 7374896 }}</ref>

Combined use of clonazepam with certain [[antidepressant]]s, [[anticonvulsant]]s (such as [[phenobarbital]], [[phenytoin]], and [[carbamazepine]]), sedative [[antihistamine]]s, [[opiate]]s, and [[antipsychotic]]s, [[nonbenzodiazepine]]s (such as [[zolpidem]]), and alcohol may result in enhanced sedative effects.<ref name="Riss-2008"/>

There is some medical evidence of various malformations (for example, cardiac or facial deformations when used in early pregnancy); however, the data is not conclusive. The data are also inconclusive on whether benzodiazepines such as clonazepam cause developmental deficits or decreases in IQ in the developing fetus when taken by the mother during pregnancy. Clonazepam, when used late in pregnancy, may result in the development of a severe benzodiazepine withdrawal syndrome in the [[Infant|neonate]]. Withdrawal symptoms from benzodiazepines in the [[Infant|neonate]] may include [[hypotonia]], [[Apnea|apnoeic]] spells, [[cyanosis]], and impaired [[Metabolism|metabolic]] responses to cold stress.<ref>{{cite journal | vauthors = McElhatton PR | title = The effects of benzodiazepine use during pregnancy and lactation | journal = Reproductive Toxicology | volume = 8 | issue = 6 | pages = 461–475 | year = 1994 | pmid = 7881198 | doi = 10.1016/0890-6238(94)90029-9 }}</ref>

The safety profile of clonazepam during pregnancy is less clear than that of other benzodiazepines, and if benzodiazepines are indicated during pregnancy, [[chlordiazepoxide]] and [[diazepam]] may be a safer choice. The use of clonazepam during pregnancy should only occur if the clinical benefits are believed to outweigh the clinical risks to the [[fetus]]. Caution is also required if clonazepam is used during breastfeeding. Possible adverse effects of use of benzodiazepines such as clonazepam during pregnancy include: [[miscarriage]], [[Birth defect|malformation]], [[Intrauterine growth restriction|intrauterine growth retardation]], functional deficits, [[carcinogenesis]], and [[mutagenesis]]. Neonatal withdrawal syndrome associated with benzodiazepines include [[hypertonia]], [[hyperreflexia]], [[anxiety|restlessness]], [[irritability]], abnormal sleep patterns, inconsolable crying, [[tremor]]s, or jerking of the extremities, [[bradycardia]], [[cyanosis]], [[Breastfeeding|suckling]] difficulties, [[apnea]], risk of aspiration of feeds, [[diarrhea]] and vomiting, and [[Delayed milestone|growth retardation]]. This syndrome can develop between three days to three weeks after birth and can have a duration of up to several months. The pathway by which clonazepam is metabolized is usually impaired in newborns. If clonazepam is used during pregnancy or [[breastfeeding]], it is recommended that serum levels of clonazepam are monitored and that signs of [[central nervous system]] depression and [[apnea]] are also checked for. In many cases, non-pharmacological treatments, such as relaxation therapy, psychotherapy, and avoidance of [[caffeine]], can be an effective and safer alternative to the use of benzodiazepines for anxiety in pregnant women.<ref>{{cite journal | vauthors = Iqbal MM, Sobhan T, Ryals T | title = Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant | journal = Psychiatric Services | volume = 53 | issue = 1 | pages = 39–49 | date = January 2002 | pmid = 11773648 | doi = 10.1176/appi.ps.53.1.39 | url = http://ps.psychiatryonline.org/cgi/content/full/53/1/39 | url-status = dead | archive-url = https://web.archive.org/web/20030711015925/http://ps.psychiatryonline.org/cgi/content/full/53/1/39 | archive-date = 11 July 2003 | url-access = subscription }}</ref>

=== Mechanism of action ===

Clonazepam enhances the activity of the inhibitory neurotransmitter [[gamma-aminobutyric acid]] (GABA) in the central nervous system to give its [[anticonvulsant]], [[Muscle relaxant|skeletal muscle relaxant]], and [[anxiolytic]] effects.<ref>{{cite web |title=FDA clonazepam |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017533s053,020813s009lbl.pdf |access-date=24 January 2019 |archive-date=5 October 2019 |archive-url=https://web.archive.org/web/20191005192927/https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017533s053,020813s009lbl.pdf |url-status=live }}</ref> It acts by binding to the benzodiazepine site of the GABA receptors, which enhances the electric effect of GABA binding on neurons, resulting in an increased influx of chloride ions into the neurons. This further results in an inhibition of synaptic transmission across the [[central nervous system]].<ref>{{cite journal | vauthors = Skerritt JH, Johnston GA | title = Enhancement of GABA binding by benzodiazepines and related anxiolytics | journal = European Journal of Pharmacology | volume = 89 | issue = 3–4 | pages = 193–198 | date = May 1983 | pmid = 6135616 | doi = 10.1016/0014-2999(83)90494-6 }}</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>

Benzodiazepines do not have any effect on the levels of GABA in the brain.<ref>{{cite journal | vauthors = Varotto M, Roman G, Battistin L | title = [Pharmacological influences on the brain level and transport of GABA. I) Effect of various antipileptic drugs on brain levels of GABA] | journal = Bollettino della Societa Italiana di Biologia Sperimentale | volume = 57 | issue = 8 | pages = 904–908 | date = April 1981 | pmid = 7272065 }}</ref> Clonazepam has no effect on GABA levels and has no effect on gamma-aminobutyric acid transaminase. Clonazepam does, however, affect [[glutamate decarboxylase]] activity. It differs from other anticonvulsant drugs it was compared to in a study.<ref>{{cite journal | vauthors = Battistin L, Varotto M, Berlese G, Roman G | title = Effects of some anticonvulsant drugs on brain GABA level and GAD and GABA-T activities | journal = Neurochemical Research | volume = 9 | issue = 2 | pages = 225–231 | date = February 1984 | pmid = 6429560 | doi = 10.1007/BF00964170 | s2cid = 34328063 }}</ref>

Clonazepam's primary [[mechanism of action]] is the modulation of [[gamma-Aminobutyric acid|GABA]] function in the brain, by the benzodiazepine receptor, located on [[GABAA receptor|GABA_A receptors]], which, in turn, leads to enhanced GABAergic inhibition of neuronal firing. Benzodiazepines do not replace GABA, but instead enhance the effect of GABA at the GABA_A receptor by increasing the opening frequency of chloride ion channels, which leads to an increase in GABA's inhibitory effects and resultant central nervous system depression.<ref name="Riss-2008"/> In addition, clonazepam decreases the utilization of [[Serotonin|5-HT (serotonin)]] by neurons<ref>{{cite journal | vauthors = Meldrum BS | title = Drugs acting on amino acid neurotransmitters | journal = Advances in Neurology | volume = 43 | pages = 687–706 | year = 1986 | pmid = 2868623 }}</ref><ref>{{cite journal | vauthors = Jenner P, Pratt JA, Marsden CD | title = Mechanism of action of clonazepam in myoclonus in relation to effects on GABA and 5-HT | journal = Advances in Neurology | volume = 43 | pages = 629–643 | year = 1986 | pmid = 2418652 }}</ref> and has been shown to bind tightly to central-type benzodiazepine receptors.<ref>{{cite journal | vauthors = Gavish M, Fares F | title = Solubilization of peripheral benzodiazepine-binding sites from rat kidney | journal = The Journal of Neuroscience | volume = 5 | issue = 11 | pages = 2889–2893 | date = November 1985 | pmid = 2997409 | pmc = 6565154 | doi = 10.1523/JNEUROSCI.05-11-02889.1985 }}</ref> Because clonazepam is effective in low milligram doses (0.5&nbsp;mg clonazepam = 10&nbsp;mg diazepam),<ref>"Benzodiazepine Equivalency Table" based on ''NRHA Drug Newsletter, April 1985 and Benzodiazepines: How they Work & How to Withdraw (The Ashton Manual), 2002.''[http://www.benzo.org.uk/bzequiv.htm] {{Webarchive|url=https://web.archive.org/web/20200729040336/https://benzo.org.uk/bzequiv.htm |date=29 July 2020 }}</ref><ref>{{Cite web|title=What are the equivalent doses of oral benzodiazepines?|url=https://www.sps.nhs.uk/articles/what-are-the-equivalent-doses-of-oral-benzodiazepines/|access-date=25 July 2020|website=SPS - Specialist Pharmacy Service|language=en-GB|archive-date=26 July 2020|archive-url=https://web.archive.org/web/20200726031136/https://www.sps.nhs.uk/articles/what-are-the-equivalent-doses-of-oral-benzodiazepines/|url-status=dead}}</ref> it is said to be among the class of "highly potent" [[benzodiazepine]]s.<ref>{{cite journal | vauthors = Chouinard G | title = Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound | journal = The Journal of Clinical Psychiatry | volume = 65 | issue = Suppl 5 | pages = 7–12 | year = 2004 | pmid = 15078112 }}</ref> The anticonvulsant properties of benzodiazepines are due to the enhancement of [[Synapse|synaptic]] GABA responses, and the inhibition of sustained, high-frequency repetitive firing.<ref>{{cite journal | vauthors = Macdonald RL, McLean MJ | title = Anticonvulsant drugs: mechanisms of action | journal = Advances in Neurology | volume = 44 | pages = 713–736 | year = 1986 | pmid = 2871724 }}</ref>

Benzodiazepines, including clonazepam, bind to mouse [[Glia|glial cell]] membranes with high affinity.<ref>{{cite journal | vauthors = Tardy M, Costa MF, Rolland B, Fages C, Gonnard P | title = Benzodiazepine receptors on primary cultures of mouse astrocytes | journal = Journal of Neurochemistry | volume = 36 | issue = 4 | pages = 1587–1589 | date = April 1981 | pmid = 6267195 | doi = 10.1111/j.1471-4159.1981.tb00603.x | s2cid = 34346051 }}</ref><ref>{{cite journal | vauthors = Gallager DW, Mallorga P, Oertel W, Henneberry R, Tallman J | title = [3H]Diazepam binding in mammalian central nervous system: a pharmacological characterization | journal = The Journal of Neuroscience | volume = 1 | issue = 2 | pages = 218–225 | date = February 1981 | pmid = 6267221 | pmc = 6564145 | doi = 10.1523/JNEUROSCI.01-02-00218.1981 | type = PDF | doi-access = free }}</ref> Clonazepam decreases release of [[acetylcholine]] in the feline brain<ref>{{cite journal | vauthors = Petkov V, Georgiev VP, Getova D, Petkov VV | title = Effects of some benzodiazepines on the acetylcholine release in the anterior horn of the lateral cerebral ventricle of the cat | journal = Acta Physiologica et Pharmacologica Bulgarica | volume = 8 | issue = 3 | pages = 59–66 | year = 1982 | pmid = 6133407 }}</ref> and decreases [[prolactin]] release in rats.<ref>{{cite journal | vauthors = Grandison L | title = Suppression of prolactin secretion by benzodiazepines in vivo | journal = Neuroendocrinology | volume = 34 | issue = 5 | pages = 369–373 | year = 1982 | pmid = 6979001 | doi = 10.1159/000123330 }}</ref> Benzodiazepines inhibit cold-induced [[thyroid-stimulating hormone]] (also known as TSH or thyrotropin) release.<ref>{{cite journal | vauthors = Camoratto AM, Grandison L | title = Inhibition of cold-induced TSH release by benzodiazepines | journal = Brain Research | volume = 265 | issue = 2 | pages = 339–343 | date = April 1983 | pmid = 6405978 | doi = 10.1016/0006-8993(83)90353-0 | s2cid = 5520697 }}</ref> Benzodiazepines act via [[Molar concentration#Units|micromolar]] benzodiazepine binding sites as [[Calcium channel blocker|Ca²⁺ channel blockers]] and significantly inhibit depolarization-sensitive calcium uptake in experimentation on rat brain cell components. This has been conjectured as a mechanism for high-dose effects on seizures in the study.<ref>{{cite journal | vauthors = Taft WC, DeLorenzo RJ | title = Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 81 | issue = 10 | pages = 3118–3122 | date = May 1984 | pmid = 6328498 | pmc = 345232 | doi = 10.1073/pnas.81.10.3118 | doi-access = free | bibcode = 1984PNAS...81.3118T }}</ref>

Clonazepam is a [[Halogenation|2'-chlorinated]] derivative of [[nitrazepam]], which increases its potency due to electron-attracting effect of the halogen in the [[Arene substitution pattern|ortho-position]].<ref>{{cite book | vauthors = Shorvon S, Perucca E, Fish D, Dodson WE |title=The Treatment of Epilepsy |date=2008 |publisher=John Wiley & Sons |isbn=9780470752456 |page=366 |url=https://books.google.com/books?id=vFQFePTM-oAC&pg=PA366 |language=en}}</ref><ref name="Coop2007"/>

=== Pharmacokinetics ===

Clonazepam is lipid-soluble, rapidly crosses the [[blood–brain barrier]], and penetrates the placenta. It is extensively metabolised into pharmacologically inactive metabolites, with only 2% of the unchanged drug excreted in the urine.<ref name="auto1">{{cite web |title=Clonazepam |url=https://www.drugbank.ca/drugs/DB01068 |website=www.drugbank.ca |access-date=24 January 2019 |archive-date=25 January 2019 |archive-url=https://web.archive.org/web/20190125020432/https://www.drugbank.ca/drugs/DB01068 |url-status=live }}</ref> Clonazepam is metabolized extensively via nitroreduction by [[cytochrome P450]] enzymes, including [[CYP3A4]]. [[Erythromycin]], [[clarithromycin]], [[ritonavir]], [[itraconazole]], [[ketoconazole]], [[nefazodone]], [[cimetidine]], and grapefruit juice are inhibitors of CYP3A4 and can affect the metabolism of benzodiazepines.<ref>{{cite journal | vauthors = Dresser GK, Spence JD, Bailey DG | title = Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition | journal = Clinical Pharmacokinetics | volume = 38 | issue = 1 | pages = 41–57 | date = January 2000 | pmid = 10668858 | doi = 10.2165/00003088-200038010-00003 | s2cid = 37743328 }}</ref> It has an [[elimination half-life]] of 19–60 hours.<ref name="Riss-2008"/> Peak blood concentrations of 6.5–13.5&nbsp;ng/mL were usually reached within 1–2 hours following a single 2&nbsp;mg oral dose of micronized clonazepam in healthy adults. In some individuals, however, peak blood concentrations were reached at 4–8 hours.<ref>{{cite web |title=Monograph - Clonazepam -- Pharmacokinetics |url=http://www.medscape.com/druginfo/monograph?cid=med&drugid=14403&drugname=Clonazepam+Oral&monotype=monograph&secid=9 |date=January 2006 |publisher=[[Medscape]] |access-date=30 December 2007 |archive-date=28 August 2021 |archive-url=https://web.archive.org/web/20210828041043/https://reference.medscape.com/ |url-status=live }}</ref>

Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum.<ref>{{cite journal | vauthors = Parry GJ | title = An animal model for the study of drugs in the central nervous system | journal = Proceedings of the Australian Association of Neurologists | volume = 13 | pages = 83–88 | year = 1976 | pmid = 1029011 }}</ref> Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.<ref>{{cite journal | vauthors = Gerna M, Morselli PL | title = A simple and sensitive gas chromatographic method for the determination of clonazepam in human plasma | journal = Journal of Chromatography | volume = 116 | issue = 2 | pages = 445–450 | date = January 1976 | pmid = 1245581 | doi = 10.1016/S0021-9673(00)89915-X }}</ref>

Clonazepam has plasma protein binding of 85%.<ref>{{cite journal | vauthors = Tokola RA, Neuvonen PJ | title = Pharmacokinetics of antiepileptic drugs | journal = Acta Neurologica Scandinavica. Supplementum | volume = 97 | pages = 17–27 | year = 1983 | pmid = 6143468 | doi = 10.1111/j.1600-0404.1983.tb01532.x | s2cid = 25137468 | doi-access = }}</ref><ref name="auto1"/> Clonazepam passes through the blood–brain barrier easily, with blood and brain levels corresponding equally with each other.<ref>{{cite journal | vauthors = Greenblatt DJ, Miller LG, Shader RI | title = Clonazepam pharmacokinetics, brain uptake, and receptor interactions | journal = The Journal of Clinical Psychiatry | volume = 48 | issue = Suppl | pages = 4–11 | date = October 1987 | pmid = 2822672 }}</ref> The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.<ref name="auto"/><ref>{{cite journal | vauthors = Edelbroek PM, De Wolff FA | title = Improved micromethod for determination of underivatized clonazepam in serum by gas chromatography | journal = Clinical Chemistry | volume = 24 | issue = 10 | pages = 1774–1777 | date = October 1978 | pmid = 699288 | doi = 10.1093/clinchem/24.10.1774 | url = http://www.clinchem.org/cgi/reprint/24/10/1774.pdf | url-status = live | type = PDF | archive-url = https://web.archive.org/web/20110607123528/http://www.clinchem.org/cgi/reprint/24/10/1774.pdf | archive-date = 7 June 2011 }}</ref> These metabolites are excreted by the kidney.<ref name="auto1"/>

It is effective for 6–8 hours in children, and 8–12 in adults.<ref>{{Cite book | url=https://books.google.com/books?id=UIUhCmMtqq8C&pg=PA214 | title=Therapeutic Uses of Botulinum Toxin| isbn=9781597452472| vauthors = Cooper G | date=5 October 2007| publisher=Springer}}</ref><ref name="Paxam_Data_Sheet" />

==Society and culture==

===Recreational use===

{{See also|Benzodiazepine misuse}}

A 2006 US government study of hospital emergency department (ED) visits found that sedative-hypnotics were the most frequently implicated pharmaceutical drug in visits, with benzodiazepines accounting for the majority of these. Clonazepam was the second most frequently implicated benzodiazepine in ED visits. Alcohol alone was responsible for over twice as many ED visits as clonazepam in the same study. The study examined the number of times the non-medical use of certain drugs was implicated in an ED visit. The criteria for non-medical use in this study were purposefully broad, and include, for example, [[Substance abuse|drug abuse]], accidental or intentional [[Drug overdose|overdose]], or adverse reactions resulting from legitimate use of the medication.<ref name=dawn2neodredv>{{cite web |url= http://www.samhsa.gov/data/DAWN/files/ED2006/DAWN2k6ED.htm |title= Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits |access-date= 9 February 2009 |year= 2006 |publisher= [[Substance Abuse and Mental Health Services Administration]] |url-status= live |archive-url= https://web.archive.org/web/20140316023656/http://www.samhsa.gov/data/DAWN/files/ED2006/DAWN2k6ED.htm |archive-date= 16 March 2014 }}</ref>

===Formulations===

Clonazepam was approved in the United States as a [[generic drug]] in 1997 and is now manufactured and marketed by several companies.

Clonazepam is available as tablets and orally disintegrating tablets (wafers) an oral solution (drops), and as a solution for injection or intravenous infusion.<ref name=":0">{{cite book | chapter = Clonazepam | veditors = Buckingham R | title = Martindale: The Complete Drug Reference | location = London | publisher = Pharmaceutical Press | url = http://www.medicinescomplete.com/ | access-date = 18 January 2019 | archive-date = 10 June 2021 | archive-url = https://web.archive.org/web/20210610002537/https://www.medicinescomplete.com/ | url-status = live }}</ref>

===Crime===

In some countries, clonazepam is used by criminals to subdue their victims.<ref>{{cite web | vauthors = Carabajal G | date = 8 December 2022 | title = Burundanga y Clonazepan. El cóctel de pastillas que usaba una "viuda negra" para doblegar a sus incautos pretendientes | trans-title = Burundanga and Clonazepan. The cocktail of pills that a "black widow" used to subdue her unwary suitors | language = Spanish | work = La Nacion | trans-work = The Nation | url = https://www.lanacion.com.ar/seguridad/burundanga-y-clonazepan-el-arsenal-de-pastillas-que-usaba-la-viuda-negra-de-los-polvorines-para-nid07122022/ | access-date = 9 December 2022 | archive-date = 9 December 2022 | archive-url = https://web.archive.org/web/20221209215126/https://www.lanacion.com.ar/seguridad/burundanga-y-clonazepan-el-arsenal-de-pastillas-que-usaba-la-viuda-negra-de-los-polvorines-para-nid07122022/ | url-status = live }}</ref>

===Brand names===

[[File:Rivotril.jpg|thumb|Brand name clonazepam tablets]]

It is marketed under the trade name Rivotril by [[Hoffmann-La Roche|Roche]] in Argentina, Australia, Austria, Bangladesh, Belgium, Brazil, Canada, Colombia, Costa Rica, Croatia, the Czech Republic, Denmark, Estonia,<ref>{{Cite web|url=http://ravimiregister.ravimiamet.ee/en/default.aspx?pv=HumRavimid.Ravim&vid=55b06c4a-7c15-4164-8f23-74317a1c28ee|title=Register of Medicinal Products|website=ravimiregister.ravimiamet.ee|access-date=18 January 2019|archive-date=28 August 2021|archive-url=https://web.archive.org/web/20210828041047/https://ravimiregister.ee/en/default.aspx?pv=HumRavimid.Ravim&vid=55b06c4a-7c15-4164-8f23-74317a1c28ee|url-status=live}}</ref> Germany, Hungary, Iceland, Ireland, Italy, China, Mexico, the Netherlands, Norway, Portugal, Peru, Pakistan, Romania, Serbia, South Africa, South Korea, Spain, Turkey, and the United States; Emcloz, Linotril, Lonazep, Clotrin and Clonotril in India and other parts of Europe; under the name Riklona in Indonesia and Malaysia; and under the trade name Klonopin by [[Hoffmann-La Roche|Roche]] in the United States. Other names, such as Antelepsin, Clonoten, Ravotril, Rivotril, Iktorivil, Clonex (Israel), Paxam, Petril, Naze, Zilepam and Kriadex, are used throughout the world.<ref name="Clonazepam International" /><ref name=":0" /> In August 2021, Roche Australia transferred Rivotril to Pharmaco Australia Ltd.<ref>{{cite web | title=Rivotril | website=NPS MedicineWise | date=13 November 2020 | url=https://www.nps.org.au/medicine-finder/rivotril-tablets | access-date=9 January 2023 | archive-date=7 March 2023 | archive-url=https://web.archive.org/web/20230307144211/https://www.nps.org.au/medicine-finder/rivotril-tablets | url-status=live }}</ref>

<gallery>

Image:klonopin0.5mg.jpg|Klonopin 0.5&nbsp;mg tablet

Image:klonopin1mg.jpg|Klonopin 1&nbsp;mg tablet

File:Clonazepam2mg DOJ.jpg|Klonopin 2&nbsp;mg tablet

File:ClonazepamODT.jpg|Clonazepam orally disintegrating tablet, 0.25&nbsp;mg

</gallery>

{{Clear}}

== References ==

{{reflist}}

== Further reading ==

== External links ==

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