Clobazam 2197412 221949727 2008-06-26T20:48:14Z Colin 381149 links {{Drugbox| | IUPAC_name = ''7-Chloro-1,5-dihydro-1-methyl-5-phenyl-<BR>1,5-benzodiazepine-2,4(3H)-dione'' | image = Clobazam-2D-skeletal.png | width = 150 | image2 = Clobazam3d.png | CAS_number = 22316-47-8 | ATC_prefix = N05 | ATC_suffix = BA09 | ATC_supplemental = | PubChem = 2789 | DrugBank = APRD00307 | C = 16 | H = 13 | Cl = 1| N = 2 | O = 2 | molecular_weight = 300.74 | bioavailability = 90% | protein_bound = 83% | metabolism = [[Liver|Hepatic]] | elimination_half-life = 18 hours | excretion = [[Kidney|Renal]] | pregnancy_category = ? | legal_status = [[Schedule IV controlled substance|Schedule IV]] (US)<br> Class C (New Zealand)<ref name=NZ_schedule>{{cite web | url=http://www.legislation.govt.nz/libraries/contents/om_isapi.dll?clientID=833759963&hitsperheading=on&infobase=pal_statutes.nfo&jd=a1975-116%2fsch.2-s.2&record={49D05730}&softpage=DOC | title=MISUSE OF DRUGS ACT 1975 | accessmonthday=28 September | accessyear=2005 }}</ref><br> Class C/Sch.4 (UK) | routes_of_administration = Oral }} '''Clobazam''' is a drug which is a [[benzodiazepine]] derivative. It has been marketed as an [[anxiolytic]] since 1975<ref name=Freche_1975>{{cite journal | first = C. | last = Freche | year = 1975 | title = [Study of an anxiolytic, clobazam, in otorhinolaryngology in psychosomatic pharyngeal manifestations] | journal = Semaine des Hopitaux. Therapeutique | volume = 51 | issue = 4 | pages = 261–3 | pmid = 5777}} [Article in French] [No abstract] [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=5777&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> and an [[anticonvulsant]] since 1984.<ref name=Anon_1984>{{cite journal | author=No authors listed | title=Clobazam in treatment of refractory epilepsy: the Canadian experience. A retrospective study. Canadian Clobazam Cooperative Group | journal=Epilepsia | volume=32 | issue=3 | year=1991 | pages=407–16 | pmid=2044502 | doi=10.1111/j.1528-1157.1991.tb04670.x}} [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=2044502&dopt=ExternalLink&ExternalLink=libs List of Library Holdings]</ref> ==Pharmacology== Clobazam is [[anticonvulsant]].<ref>{{cite journal | journal = Life Sci | year = 1985| month = Feb| date = 25| volume = 36| issue = 8| pages = 737–44| title = Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines| author = Chweh AY| coauthors = Swinyard EA, Wolf HH, Kupferberg HJ| pmid = 2983169| doi = 10.1016/0024-3205(85)90193-6}}</ref> Clobazam is a 1,5-benzodiazepine, meaning that its [[diazepine]] ring has [[nitrogen]] atoms at the 1 and 5 positions (instead of the usual 1 and 4). Like other 1,5-benzodiazepines ([[arfendazam]], [[lofendazam]], e.g.), it has less [[affinity]] for the ω<sub>1</sub>-[[allosteric]] binding site on the [[GABA A receptor|GABA<sub>A</sub> receptor]] compared to the 1,4-benzodiazepines. It has selective affinity for the ω<sub>2</sub> site, where it has [[agonist]]ic activity.<ref name=omega2>{{cite journal | author=Nakajima H | title=[A pharmacological profile of clobazam (Mystan), a new antiepileptic drug] | journal=Nippon Yakurigaku Zasshi | volume=118 | issue=2 | year=2001 | pages=117–22 | pmid=11530681 | url = http://www.jstage.jst.go.jp/article/fpj/118/2/117/_pdf | format = PDF}} [Article in Japanese]</ref> In a double-blind placebo-controlled trial published in 1990 comparing it to [[clonazepam]], 10mg or 20 mg of clobazam was shown to be much less sedating than either 0.5mg or 1 mg of clonazepam.<ref name=vsclonazepam>{{cite journal | author=Wildin JD, Pleuvry BJ, Mawer GE, Onon T, Millington L | title=Respiratory and sedative effects of clobazam and clonazepam in volunteers | journal=British Journal of Clinical Pharmacology | volume=29 | issue=2 | year=1990 | pages=169–77 | pmid=2106335 }}[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=2106335&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> The ω<sub>1</sub>-receptor, which is found on the α<sub>1</sub> subtype of the GABA<sub>A</sub> receptor, was shown to be responsible for the sedative effects of [[diazepam]] by McKernan et al in 2000, who also showed that its anxiolytic and anticonvulsant properties could still be seen in mice whose α<sub>1</sub> receptors were insensitive to diazepam.<ref name=McKernan>{{cite journal | author=McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, Farrar S, Myers J, Cook G, Ferris P, Garrett L, Bristow L, Marshall G, Macaulay A, Brown N, Howell O, Moore KW, Carling RW, Street LJ, Castro JL, Ragan CI, Dawson GR, Whiting PJ | title=Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype | journal=Nature Neuroscience | volume=3 | issue=6 | year=2000 | pages=587–92 | pmid=10816315 | doi = 10.1038/75761 | url = http://www.nature.com/neuro/journal/v3/n6/full/nn0600_587.html}}</ref> It would seem, then, that the anticonvulsant properties of clobazam are due to its selective affinity for ω<sub>2</sub>. In 1996, Nakamura et al reported that clobazam and its active metabolite, N-desmethylclobazam (norclobazam), work by enhancing [[gamma-aminobutyric acid|GABA]]-activated [[chloride]] currents at GABA<sub>A</sub>-receptor-coupled [[ion channel|Cl<sup>-</sup> channel]]s. It was also reported that these effects were inhibited by the GABA [[antagonist]] [[flumazenil]], and that clobazam acts most efficiently in GABA-deficient [[brain]] tissue.<ref name=Nakamura_et_al_1996>{{cite journal | first = Fumihiro | last = Nakamura | coauthors = Suzuki Setsuo, Nishimura Shigeko, Yagi Kazuichi, and Seino Masakazu | title = Effects of clobazam and its active metabolite on GABA-activated currents in rat cerebral neurons in culture | journal = Epilepsia | volume = 37 | issue = 8 | year = 1996 | pages = 728–35 | pmid = 8764810 | url = http://www.blackwell-synergy.com/doi/pdf/10.1111/j.1528-1157.1996.tb00643.x | format = PDF | accessdate = 2006-08-03 | doi = 10.1111/j.1528-1157.1996.tb00643.x}}</ref> ===Metabolism=== Clobazam has two major metabolites: N-desmethyl-clobazam and 4'-hydroxyclobazam, the former of which is active.<ref name=active-metabolite>{{cite journal | author=Contin M, Sangiorgi S, Riva R, Parmeggiani A, Albani F, Baruzzi A | title=Evidence of polymorphic CYP2C19 involvement in the human metabolism of N-desmethylclobazam | journal=Therapeutic Drug Monitoring | volume=24 | issue=6 | year=2002 | pages=737–41 | pmid=12451290 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=12451290&dopt=ExternalLink | doi=10.1097/00007691-200212000-00009}} [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=12451290&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> The demethylation is facilitated by [[CYP2C19]], [[CYP3A4]], and [[CYP2B6]] and the 4'-hydroxyclobazam by [[CYP2C18]] and CYP2C19.<ref name=Giraudetal2004>{{cite journal | author=Giraud C, Tran A, Rey E, Vincent J, Treluyer JM, Pons G | title=In vitro characterization of clobazam metabolism by recombinant cytochrome P450 enzymes: importance of CYP2C19 | journal=Drug Metabolism and Disposition | volume=32 | issue=11 | year=2004 | pages=1279–86 | pmid=15483195 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=15483195&dopt=ExternalLink}} [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=15483195&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> ==Tolerance and dependence== In humans tolerance to the anticonvulsant effects of clobazam frequently occurs.<ref>{{cite journal |author=Loiseau P |year =1983 |title =[Benzodiazepines in the treatment of epilepsy] | journal =Encephale | volume =9 | issue =4 Suppl 2 | pages =287B–292B | pmid = 6373234 }}</ref> Clobazam as with other [[benzodiazepine]] drugs can lead to [[physical dependence]], [[addiction]] and what is known as the [[benzodiazepine withdrawal syndrome]]. Withdrawal from clobazam or other benzodiazepines after regular use often leads to withdrawal symptoms which are similar to those seen during alcohol and [[barbiturate]] withdrawal. The higher the dose and the longer the drug is taken for, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can however occur from standard dosages and also after short term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.<ref>{{cite journal | author = MacKinnon GL | coauthors = Parker WA. | year = 1982 | month = | title = Benzodiazepine withdrawal syndrome: a literature review and evaluation. | journal = The American journal of drug and alcohol abuse. | volume = 9 | issue = 1 | pages = 19–33 | pmid = 6133446| doi = 10.3109/00952998209002608 }}</ref> ==Indications== As of 2005, clobazam (Frisium) is approved in Canada for adjunctive use in tonic-clonic, complex partial, and myoclonic seizures.<ref name=clobazam_canada>{{cite web | author = Epilepsy Ontario | year = 2005 | url = http://epilepsyontario.org/client/eo/EOWeb.nsf/web/clobazam | title = Clobazam | work = Medications | accessdate = 2006-03-04}}</ref> Clobazam (Urbanyl<ref name=French_tradename>{{cite web | url=http://www.vidal.fr/substance/clobazam-1009.htm | title=Liste des médicaments contenant la substance: Clobazam | accessdate=2005-09-28 }} Vidal.</ref>) is approved for adjunctive therapy in [[seizure|complex partial seizure]]s<ref name=complexpartialfrance>{{cite journal | author=Larrieu JL, Lagueny A, Ferrer X, Julien J | title=[Epilepsy with continuous discharges during slow-wave sleep. Treatment with clobazam] | journal=Revue d'Electroencephalographie et de Neurophysiologie Clinique | volume=16 | issue=4 | year=1986 | pages=383–94}} [Article in French] PMID 3103177 [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=3103177&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> certain types of [[status epilepticus]], specifically the [[myoclonic seizure|myoclonic]], [[myoclonic seizure|myoclonic]]-[[absence seizure|absent]], [[simple partial seizure|simple partial]], [[complex partial seizure|complex partial]], and tonic varieties,<ref name=statusepilepticus>{{cite journal | first = Henri | last = Gastaut | coauthors = Tinuper P, Aguglia U, Lugaresi E | title=[Treatment of certain forms of status epilepticus by means of a single oral dose of clobazam] | journal=Revue d'Electroencephalographie et de Neurophysiologie Clinique | volume=14 | issue=3 | year=1984 | pages=203–6 | pmid = 6528075}}</ref> and non-status absence seizures.<ref name=other_French_approvals>{{cite web | author=Biam Database | year=2001 | title=CLOBAZAM | work=Classes Chimiques: BENZODIAZEPINE | url=http://www.biam2.org/www/Sub1282.html | accessdate = 2005-09-28}}</ref> It is also approved for treatment of anxiety. In India, clobazam (Frisium, Aventis Pharma India, Ltd.) is approved for use as an adjunctive therapy in epilepsy and in acute and chronic [[anxiety]].<ref name=aventispharmaindia>{{cite web | url=http://www.aventispharmaindia.com/presskitsFrisium.htm | title=Frisium Press Kit | publisher = Aventis Pharma India | accessdate = 2006-08-02 |archiveurl = http://web.archive.org/web/20050305135005/http://www.aventispharmaindia.com/presskitsFrisium.htm | archivedate = 2005-03-05}}</ref> In Japan, clobazam (Mystan<ref name=omega2 />) is approved for adjunctive therapy in treatment-resistant [[epilepsy]] featuring [[seizure|complex partial seizure]]s.<ref name=complexpartial>{{cite journal | first = Hisako | last = Shimizu | coauthors = Kawasaki Jun, Yuasa Shoji, Tarao Yoko, [[Kumagai Sachiyo]], Kanemoto Kousuke | title=Use of clobazam for the treatment of refractory complex partial seizures | journal=Seizure | volume=12 | issue=5 | year=2003 | pages=282–6 | pmid=12810340 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=12810340&dopt=ExternalLink | doi=10.1016/S1059-1311(02)00287-X}} [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=12810340&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> In New Zealand, clobazam is marketed as Frisium<ref name=nzfrisium>{{cite web | author=Epilepsy New Zealand | year=2000 | url=http://www.epilepsy.org.nz/sheets.cfm?SheetID=13&PageName=Antiepileptic%20Medication | title=Antiepileptic Medication | accessdaymonth=11 July | accessyear=2005}}</ref> In the United Kingdom, clobazam (Frisium) is approved in the United Kingdom for short-term (2-4 weeks) relief of acute anxiety in patients who have not responded to other drugs, with or without insomnia and without uncontrolled [[clinical depression]].<ref name=clobazam_anxiety_UK>{{cite web | author=sanofi-aventis | year=2002 | title=Frisium Tablets 10 mg, Summary of Product Characteristics from eMC | work=electronic Medicines Compendium | publisher=Medicines.org.uk | url=http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=8298 | accessdaymonth=11 July | accessyear=2005}}</ref> It is also approved for adjunctive therapy for epilepsy in patients who have not responded to first-line drugs and in children who are refractory to first-line drugs. It is not recommended for use in children between the ages of six months and three years, unless there is a compelling need.<ref name=clobazam_anxiety_UK /> In addition to epilepsy and severe anxiety, clobazam is also approved as an adjunctive agent in [[schizophrenia]] and other [[psychotic disorder]]s.<ref name=clobazam_anxiety_UK /> Clobazam is sometimes used for refractory epilepsies however, long term prophylactic treatment of epilepsy has considerable drawbacks, most importantly loss of antiepileptic effects due to tolerance which may render long term therapy useless.<ref>{{cite journal | last = Isojärvi | first = JI | coauthors = Tokola RA. | year = 1998 | month = Dec | title = Benzodiazepines in the treatment of epilepsy in people with intellectual disability. | journal = J Intellect Disabil Res. | volume = 42 | issue = 1 | pages = 80–92 | pmid = 10030438 }}</ref> Other antiepileptic drugs may therefore be preferred for the long term management of epielpsy. Also benzodiazepines have the draw back after long term use of causing rebound seizures upon abrupt or over-rapid discontinuation of therapy forming part of the [[benzodiazepine withdrawal syndrome]]. ==Dosage== Clobazam is available in oral form only, due to its insolubility in water. ==Side effects== ===Common=== *[[Ataxia]] *[[Somnolence]] *[[Diplopia]] *[[Dysarthria]] ===Rare=== *[[Gelastic seizure]]s<ref name=|gelastic>{{cite journal | author=Iwasaki T | coauthors = Miura H, Sunaoshi W, Hosoda N, Takei K, Katayama F | title=[A case of intractable epilepsy showing frequent gelastic seizures by administration of clobazam] | journal=No To Hattatsu | volume=35 | issue=5 | year=2003 | pages=406–10}} [Article in Japanese] PMID 13677950 [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=13677950&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> *[[Urticaria]] *[[Rash]]es ==Contraindications== Clobazam should be used with great care in patients with the following disorders: *[[Myasthenia gravis]] *[[Sleep apnea]] *Severe [[liver]] diseases such as [[cirrhosis]] and [[hepatitis]]<ref name=clobazamliver>{{cite journal | author=Monjanel-Mouterde S, Antoni M, Bun H, Botta-Frindlund D, Gauthier A, Durand A, Cano JP | title=Pharmacokinetics of a single oral dose of clobazam in patients with liver disease | journal=Annual Review of Pharmacology and Toxicology | volume=74 | issue=6 | year=1994 | pages=345–50 | pmid=7937568}} [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=7937568&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> *[[Respiration (physiology)|Respiratory]] problems, including [[hypoventilation]] ===Drug Interactions=== *[[Alcohol]] increases bioavailability by 50% *[[Cimetidine]] increases the effects of clobazam *[[valproic acid|valproate]]s ==Abuse potential== Clobazam in animal studies has been shown to increase reward seeking behaviours which may suggest an increased risk of addictive behavioural patterns.<ref>{{cite journal | author = Thiébot MH | coauthors = Le Bihan C, Soubrié P, Simon P. | year = 1985 | month = | title = Benzodiazepines reduce the tolerance to reward delay in rats. | volume = 86 | issue = 1-2 | pages = 147–52 | pmid = 2862657 | journal = Psychopharmacology (Berl).| doi = 10.1007/BF00431700}}</ref> ==External links== *[http://www.inchem.org/documents/pims/pharm/pim921.htm Inchem - Clobazam] *[http://med.ds-pharma.co.jp/medicine/ryouiki/seishin/doc/mystan_tabfgr_tenpu.pdf Mystan Prescribing Information Sheet] (Japanese) ==References== *{{cite web | author=Ochoa, Juan G. | year=2005 | title=GABA Receptor Agonists | work=Antiepileptic Drugs: An Overview | publisher=eMedicine.com, Inc | url=http://www.emedicine.com/neuro/topic692.htm#section~gaba_receptor_agonists | accessdaymonth=10 July | accessyear=2005}} ==End Notes== {{reflist|2}} {{Benzodiazepines}} {{Anticonvulsants}} {{Anxiolytics}} [[Category:Benzodiazepines]] [[Category:Hypnotics]] [[ja:クロバザム]] [[pt:Clobazam]] [[ru:Клобазам]] [[fi:Klobatsaami]]