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Clobazam

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Clobazam
Clinical data
Trade namesFrisium, Urbanol, Onfi, others
AHFS/Drugs.comMonograph
MedlinePlusa612008
License data
Pregnancy
category
  • AU:C
Routes of
administration		By mouth
Drug classBenzodiazepine
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability87% (oral)
Protein binding80–90%
MetabolismLiver
Metabolites
    • N-desmethylclobazam
    • 4′-hydroxyclobazam
Onset of action0.5–4 hours
Eliminationhalf-life
    • clobazam: 36–42 hours
    • N-desmethylclobazam: 59–82 hours
Excretion
Identifiers
  • 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.040.810Edit this at Wikidata
Chemical and physical data
FormulaC16H13ClN2O2
Molar mass300.74g·mol−1
3D model (JSmol)
  • ClC1=CC(N(C2=CC=CC=C2)C(CC(N3C)=O)=O)=C3C=C1
  • InChI=1S/C16H13ClN2O2/c1-18-13-8-7-11(17)9-14(13)19(16(21)10-15(18)20)12-5-3-2-4-6-12/h2-9H,10H2,1H3checkY
  • Key:CXOXHMZGEKVPMT-UHFFFAOYSA-NcheckY
(verify)

Clobazam,sold under the brand namesFrisium,Onfiand others, is abenzodiazepineclass medication that was patented in 1968.[3]Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxioselectiveanxiolyticsince 1970,[4][5]and ananticonvulsantsince 1984.[6]The primary drug-development goal was to provide greater anxiolytic, anti-obsessive efficacy with fewer benzodiazepine-related side effects.[4]

Medical uses

[edit]

Clobazam is used for itsanxiolyticeffect, and as anadjunctive therapyinepilepsy.

As an adjunctive therapy in epilepsy, it is used in patients who have not responded to first-line drugs and in children who are refractory to first-line drugs. It is unclear if there are any benefits to clobazam over other seizure medications for children withRolandic epilepsyor other epileptic syndromes.[7]It is not recommended for use in children between the ages of six months and three years, unless there is a compelling need.[8]In addition to epilepsy and severe anxiety, clobazam is approved in theUnited Kingdomas a short-term (2–4 weeks) adjunctive agent inschizophreniaand otherpsychotic disordersto manageanxietyoragitation.[8][9]

Clobazam is sometimes used for refractory epilepsies. However, long-term prophylactic treatment of epilepsy may have considerable drawbacks, most importantly decreased antiepileptic effects due todrug tolerancewhich may render long-term therapy less effective.[10]Other antiepileptic drugs may therefore be preferred for the long-term management of epilepsy. Furthermore, benzodiazepines may have the drawback, particularly after long-term use, of causing rebound seizures upon abrupt or over-rapid discontinuation of therapy forming part of thebenzodiazepine withdrawal syndrome.

Clobazam is approved in Canada for add-on use intonic-clonic,complex partial,andmyoclonic seizures.[11]Clobazam is approved for adjunctive therapy in complex partial seizures,[12]certain types ofstatus epilepticus,specifically themyoclonic,myoclonic-absent,simple partial,complex partial,and tonic varieties,[13]and non-statusabsence seizures.It is also approved for the treatment of anxiety.

In India, clobazam is approved for use as an adjunctive therapy in epilepsy, and in acute and chronicanxiety.[14]In Japan, clobazam is approved for adjunctive therapy in treatment-resistantepilepsyfeaturing complex partial seizures.[15]In New Zealand, clobazam is marketed as Frisium[16]In the United Kingdom clobazam (Frisium) is approved 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 uncontrolledclinical depression.[8]It was not approved in the United States until 25 October 2011, when it was approved for the adjunctive treatment of seizures associated withLennox-Gastaut syndromein patients 2 years of age or older.[17]

The currentFDAindicated for use in combination with other medicines is to control seizures in adults and children 2 years and older who have a specific severe form of epilepsy called Lennox-Gastaut syndrome. Clobazam has been FDA-approved for 12 years as of 2023[18]and it is available in multiple formulations under the brand names Onfi and Sympazan as well as generic formulations.

Contraindications

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Clobazam should be used with great care in patients with the following disorders:

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals, and individuals withcomorbidpsychiatric disorders.[20]

Side effects

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In September 2020, the U.S.Food and Drug Administration(FDA) required theboxed warningbe 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.[21]

Common

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Common side effects include fever, drooling, and constipation.[22]

Post-marketing experience

[edit]

Warnings and precautions

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In December 2013, theFDAadded warnings to the label for clobazam, that it can cause serious skin reactions,Stevens–Johnson syndrome,andtoxic epidermal necrolysis,especially in the first eight weeks of treatment.[23]

Drug interactions

[edit]
  • Alcoholincreases bioavailability by 50%; compounded depressant effect may precipitate life-threatening toxicity.
  • Cimetidineincreases the effects of clobazam.
  • Valproate.

Overdose

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Overdose and intoxication with benzodiazepines, including clobazam, may lead toCNS depression,associated with drowsiness, confusion, and lethargy, possibly progressing toataxia,respiratory depression,hypotension, and coma or death. The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including alcohol.[24]

Abuse potential and addiction

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See also:Benzodiazepine use disorder

Classic (non-anxioselective) benzodiazepines in animal studies have been shown to increase reward-seeking behaviours which may suggest an increased risk of addictive behavioural patterns.[25]Clobazam abuse has been reported in some countries, according to a 1983 World Health Organization report.[26]

Dependence and withdrawal

[edit]

In humans, tolerance to the anticonvulsant effects of clobazam may occur[27]and withdrawal seizures may occur during abrupt or over-rapid withdrawal.[28]

Clobazam as with otherbenzodiazepinedrugs can lead tophysical dependence,addiction,and what is known as thebenzodiazepine withdrawal syndrome.Withdrawal from clobazam or other benzodiazepines after regular use often leads to withdrawal symptoms which are similar to those seen during alcohol andbarbituratewithdrawal. The higher the dosage and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Benzodiazepine treatment should only be discontinued via a slow and gradual dose reduction regimen.[29]

Pharmacology

[edit]

Clobazam is predominantly apositive allosteric modulatorat theGABAAreceptorwith some speculated additional activity atsodium channelsandvoltage-sensitive calcium channels.[30]

Like other 1,5-benzodiazepines (for example,arfendazam,lofendazam,orCP-1414S), the active metaboliteN-desmethylclobazam has lessaffinityfor theα1subunitof theGABAAreceptorcompared to the 1,4-benzodiazepines. It has higher affinity forα2containing receptors, where it has positive modulatory activity.[31][32]

In a double-blind placebo-controlled trial published in 1990 comparing it toclonazepam,10 mg of clobazam was shown to be lesssedativethan either 0.5 mg or 1 mg of clonazepam.[33]

The α1subtype of the GABAAreceptor, was shown to be responsible for the sedative effects ofdiazepamby McKernan et al. in 2000, who also showed that its anxiolytic and anticonvulsant properties could still be seen in mice whose α1receptors were insensitive to diazepam.[34]

In 1996, Nakamura et al. reported that clobazam and its active metabolite,N-desmethylclobazam (norclobazam), work by enhancingGABA-activatedchlorideinflux at GABAAreceptors,[35]creating ahyperpolarizing,inhibitory postsynaptic potential.[36]It was also reported that these effects were inhibited by theGABA antagonistflumazenil,and that clobazam acts more efficiently in GABA-deficient brain tissue.[35]

Metabolism

[edit]

Clobazam has two major metabolites:N-desmethylclobazam and 4′-hydroxyclobazam, the former of which is active.[37]The demethylation is facilitated byCYP2C19,CYP3A4,andCYP2B6and the4-hydroxyclobazam byCYP2C18and CYP2C19.[38]

In children, clobazam half-life values is average 16 hours, while in the elderly, clobazam half-life values are 30 to 48 hours.[39][40]

Chemistry

[edit]

Clobazam is a 1,5-benzodiazepine, meaning that itsdiazepinering hasnitrogenatoms at the 1 and 5 positions (instead of the usual 1 and 4).[41]

It is not soluble in water and is available in oral form only.[30][24]

History

[edit]

Clobazam was discovered at the Maestretti Research Laboratories in Milan and was first published in 1969;[42]Maestretti was acquired byRoussel Uclaf[43]which became part ofSanofi.

References

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  1. ^"FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)".nctr-crs.fda.gov.FDA.Retrieved22 October2023.
  2. ^Anvisa(31 March 2023)."RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial"[Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese).Diário Oficial da União(published 4 April 2023).Archivedfrom the original on 3 August 2023.Retrieved16 August2023.
  3. ^"Clobazam (T3D4564)".Toxin and Toxin Target Database (T3DB.
  4. ^abHumayun MJ, Samanta D, Carson RP (2020). "Clobazam".StatPearls.Treasure Island (FL): StatPearls Publishing.PMID31082087.
  5. ^Freche C (April 1975). "[Study of an anxiolytic, clobazam, in otorhinolaryngology in psychosomatic pharyngeal manifestations]".Semaine des Hopitaux. Therapeutique.51(4): 261–3.PMID5777.
  6. ^"Clobazam in treatment of refractory epilepsy: the Canadian experience. A retrospective study. Canadian Clobazam Cooperative Group".Epilepsia.32(3): 407–16. 1991.doi:10.1111/j.1528-1157.1991.tb04670.x.PMID2044502.S2CID24420211.
  7. ^Arya R, Giridharan N, Anand V, Garg SK (July 2018)."Clobazam monotherapy for focal or generalized seizures".The Cochrane Database of Systematic Reviews.2018(7): CD009258.doi:10.1002/14651858.CD009258.pub3.PMC6513499.PMID29995989.
  8. ^abcsanofi-aventis (2002)."Frisium Tablets 10 mg, Summary of Product Characteristics from eMC".electronic Medicines Compendium.Medicines.org.uk. Archived fromthe originalon 6 December 2007.Retrieved11 July2005.
  9. ^"Clobazam 10 mg Tablets - Summary of Product Characteristics (SmPC) - (emc)".www.medicines.org.uk.Retrieved19 January2024.
  10. ^Isojärvi JI, Tokola RA (December 1998). "Benzodiazepines in the treatment of epilepsy in people with intellectual disability".Journal of Intellectual Disability Research.42(Suppl 1): 80–92.PMID10030438.
  11. ^"Clobazam".Epilepsy Ontario.2020.Retrieved21 August2020.
  12. ^Larrieu JL, Lagueny A, Ferrer X, Julien J (December 1986). "[Epilepsy with continuous discharges during slow-wave sleep. Treatment with clobazam]".Revue d'Electroencephalographie et de Neurophysiologie Clinique(in French).16(4): 383–94.doi:10.1016/S0370-4475(86)80028-4.PMID3103177.
  13. ^Gastaut H, Tinuper P, Aguglia U, Lugaresi E (December 1984). "[Treatment of certain forms of status epilepticus by means of a single oral dose of clobazam]".Revue d'Electroencephalographie et de Neurophysiologie Clinique.14(3): 203–6.doi:10.1016/S0370-4475(84)80005-2.PMID6528075.
  14. ^"Frisium Press Kit".Aventis Pharma India. Archived fromthe originalon 5 March 2005.Retrieved2 August2006.
  15. ^Shimizu H, Kawasaki J, Yuasa S, Tarao Y, Kumagai S, Kanemoto K (July 2003)."Use of clobazam for the treatment of refractory complex partial seizures".Seizure.12(5): 282–6.doi:10.1016/S1059-1311(02)00287-X.PMID12810340.
  16. ^Epilepsy New Zealand (2000)."Antiepileptic Medication".Archived fromthe originalon 11 March 2005.Retrieved11 July2005.
  17. ^"FDA Approves ONFI™ (clobazam) for the Adjunctive Treatment of Seizures Associated with Lennox-Gastaut Syndrome in Patients Two Years and Older"(Press release). Lundbeck.Retrieved25 October2011.
  18. ^SYMPAZAN: HIGHLIGHTS OF PRESCRIBING INFORMATION, FDA.
  19. ^Monjanel-Mouterde S, Antoni M, Bun H, Botta-Frindlund D, Gauthier A, Durand A, et al. (June 1994). "Pharmacokinetics of a single oral dose of clobazam in patients with liver disease".Pharmacology & Toxicology.74(6): 345–50.doi:10.1111/j.1600-0773.1994.tb01371.x.PMID7937568.
  20. ^Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, et al. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome".Annales Pharmaceutiques Françaises.67(6): 408–13.doi:10.1016/j.pharma.2009.07.001.PMID19900604.
  21. ^"FDA expands Boxed Warning to improve safe use of benzodiazepine drug".U.S.Food and Drug Administration(FDA).23 September 2020.Retrieved23 September2020.Public DomainThis article incorporates text from this source, which is in thepublic domain.
  22. ^"Clobazam label"(PDF).December 2014.
  23. ^FDA. 3 December 2013FDA Drug Safety Podcast: FDA warns of serious skin reactions with the anti-seizure drug Onfi (clobazam) and has approved label changes
  24. ^abFruchtengarten LInchem - Clobazam.Created July 1997, Reviewed 1998.
  25. ^Thiébot MH, Le Bihan C, Soubrié P, Simon P (1985). "Benzodiazepines reduce the tolerance to reward delay in rats".Psychopharmacology.86(1–2): 147–52.doi:10.1007/BF00431700.PMID2862657.S2CID30614502.
  26. ^WHO Review Group (1983)."Use and abuse of benzodiazepines".Bulletin of the World Health Organization.61(4): 551–62.PMC2536139.PMID6605211.
  27. ^Loiseau P (1983). "[Benzodiazepines in the treatment of epilepsy]".L'Encéphale.9(4 Suppl 2): 287B–292B.PMID6373234.
  28. ^Robertson MM (1986). "Current status of the 1,4- and 1,5-benzodiazepines in the treatment of epilepsy: the place of clobazam".Epilepsia.27(Suppl 1): S27-41.doi:10.1111/j.1528-1157.1986.tb05730.x.PMID3527689.S2CID23166797.
  29. ^MacKinnon GL, Parker WA (1982). "Benzodiazepine withdrawal syndrome: a literature review and evaluation".The American Journal of Drug and Alcohol Abuse.9(1): 19–33.doi:10.3109/00952998209002608.PMID6133446.
  30. ^abOchoa JG (2005)."Antiepileptic Drugs: An Overview. GABA Receptor Agonists".Drugs and Diseases.Medccape.Retrieved10 July2005.
  31. ^Ralvenius WT, Acuña MA, Benke D, Matthey A, Daali Y, Rudolph U, et al. (October 2016)."The clobazam metabolite N-desmethyl clobazam is an α2 preferring benzodiazepine with an improved therapeutic window for antihyperalgesia".Neuropharmacology.109:366–375.doi:10.1016/j.neuropharm.2016.07.004.PMC4981430.PMID27392635.
  32. ^Nakajima H (August 2001)."[A pharmacological profile of clobazam (Mystan), a new antiepileptic drug]".Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica.118(2): 117–22.doi:10.1254/fpj.118.117.PMID11530681.
  33. ^Wildin JD, Pleuvry BJ, Mawer GE, Onon T, Millington L (February 1990)."Respiratory and sedative effects of clobazam and clonazepam in volunteers".British Journal of Clinical Pharmacology.29(2): 169–77.doi:10.1111/j.1365-2125.1990.tb03616.x.PMC1380080.PMID2106335.
  34. ^McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, et al. (June 2000). "Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype".Nature Neuroscience.3(6): 587–92.doi:10.1038/75761.PMID10816315.S2CID10340592.
  35. ^abNakamura F, Suzuki S, Nishimura S, Yagi K, Seino M (August 1996). "Effects of clobazam and its active metabolite on GABA-activated currents in rat cerebral neurons in culture".Epilepsia.37(8): 728–35.doi:10.1111/j.1528-1157.1996.tb00643.x.PMID8764810.S2CID12628361.
  36. ^Tolbert D, Larsen F (January 2019)."A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam".Journal of Clinical Pharmacology.59(1): 7–19.doi:10.1002/jcph.1313.PMC6585772.PMID30285275.
  37. ^Contin M, Sangiorgi S, Riva R, Parmeggiani A, Albani F, Baruzzi A (December 2002). "Evidence of polymorphic CYP2C19 involvement in the human metabolism of N-desmethylclobazam".Therapeutic Drug Monitoring.24(6): 737–41.doi:10.1097/00007691-200212000-00009.PMID12451290.S2CID44444755.
  38. ^Giraud C, Tran A, Rey E, Vincent J, Tréluyer JM, Pons G (November 2004). "In vitro characterization of clobazam metabolism by recombinant cytochrome P450 enzymes: importance of CYP2C19".Drug Metabolism and Disposition.32(11): 1279–86.doi:10.1124/dmd.32.11.1279.PMID15483195.S2CID6490031.
  39. ^Patsalos PN (2022). "Clobazam". In Patsalos PN (ed.).Antiseizure Medication Interactions: A Clinical Guide.Cham: Springer International Publishing. pp. 55–59.doi:10.1007/978-3-030-82790-8_7.ISBN978-3-030-82790-8.
  40. ^Ng YT, Collins SD (January 2007)."Clobazam".Neurotherapeutics.New Antiepileptic Drugs: Discovery, Development, and Update.4(1): 138–144.doi:10.1016/j.nurt.2006.11.002.PMC7479695.PMID17199029.
  41. ^Shorvon SD (March 2009)."Drug treatment of epilepsy in the century of the ILAE: the second 50 years, 1959-2009".Epilepsia.50(Suppl 3): 93–130.doi:10.1111/j.1528-1167.2009.02042.x.PMID19298435.S2CID20445985.
  42. ^Hanks GW (1979)."Clobazam: pharmacological and therapeutic profile".British Journal of Clinical Pharmacology.7(Suppl 1): 151S–155S.doi:10.1111/j.1365-2125.1979.tb04685.x.PMC1429523.PMID35198.
  43. ^Zirulia G (2014).L'industria delle Medicine.EDRA LSWR.ISBN9788821439049.

Further reading

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Retrieved from "https://en.wikipedia.org/w/index.php?title=Clobazam&oldid=1234451603"