Clobazam

Not to be confused with clonazepam.

Clobazam

Systematic (IUPAC) name
7-Chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4(3H)-dione
Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Licence data	US FDA:link
Pregnancy cat.	C(US)
Legal status	Schedule IV (US) Class C (New Zealand)[1] Class C/Sch.4 (UK)
Routes	Oral
Pharmacokinetic data
Bioavailability	90%
Protein binding	83%
Metabolism	Hepatic
Half-life	18 hours
Excretion	Renal
Identifiers
CAS number	22316-47-8 Y
ATC code	N05BA09
PubChem	CID 2789
DrugBank	APRD00307
ChemSpider	2687 Y
UNII	2MRO291B4U Y
KEGG	D01253 Y
ChEBI	CHEBI:31413 Y
ChEMBL	CHEMBL70418 Y
Chemical data
Formula	C16H13ClN2O2
Mol. mass	300.74
SMILES	eMolecules & PubChem
InChI 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,10H2,1H3 Y Key:CXOXHMZGEKVPMT-UHFFFAOYSA-N Y
N(what is this?)  (verify)

Clobazam^[2] (marketed under the brand names Frisium, Urbanol and Onfi), is a drug which is a benzodiazepine derivative. It has been marketed as an anxiolytic since 1975^[3] and an anticonvulsant since 1984.^[4] It has also been used incorrectly in combination with several injectable contraceptives^{[citation needed]}.

Indications

As of 2005, clobazam (Frisium) is approved in Canada for adjunctive use in tonic-clonic, complex partial, and myoclonic seizures.^[5] Clobazam (Urbanyl^[6]) is approved for adjunctive therapy in complex partial seizures^[7] certain types of status epilepticus, specifically the myoclonic, myoclonic-absent, simple partial, complex partial, and tonic varieties,^[8] and non-status absence seizures.^[9] 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.^[10] In Japan, clobazam (Mystan^[11]) is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures.^[12] In New Zealand, clobazam is marketed as Frisium^[13] 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 uncontrolled clinical depression.^[14] It was not approved in the US until October 25, 2011, when it was approved for the treatment of seizures associated with Lennox-Gastaut Syndrome.^[15]

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.^[14] In addition to epilepsy and severe anxiety, clobazam is also approved as a short term (2–4 weeks) adjunctive agent in schizophrenia and other psychotic disorders to manage anxiety or agitation.^[14]

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 ineffective.^[16] Other antiepileptic drugs may therefore be preferred for the long term management of epilepsy. Furthermore, benzodiazepines have the drawback, particularly after long-term use, of causing rebound seizures upon abrupt or over-rapid discontinuation of therapy forming part of the benzodiazepine withdrawal syndrome.

Availability

Clobazam is available in oral form only, due to its insolubility in water.

Side effects

Common

• Ataxia
• Somnolence
• Diplopia
• Dysarthria

Rare

• Gelastic seizures^[17]
• Urticaria
• Rashes

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^[18]
• Respiratory problems, including hypoventilation

Special caution

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.^[19]

Tolerance and dependence

In humans tolerance to the anticonvulsant effects of clobazam frequently occurs^[20] and withdrawal seizures can occur during abrupt or overrapid withdrawal.^[21]

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.^[22]

Pharmacology

Clobazam is an anticonvulsant.^[23] 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 (e.g., arfendazam, lofendazam, CP-1414S), it has less affinity for the ω₁-allosteric binding site on the GABA_A receptor compared to the 1,4-benzodiazepines. It has selective affinity for the ω₂ site, where it has agonistic activity.^[11]

In a double-blind placebo-controlled trial published in 1990 comparing it to clonazepam, 10 mg or 20 mg of clobazam was shown to be much less sedating than either 0.5 mg or 1 mg of clonazepam.^[24]

The ω₁-receptor, which is found on the α₁ subtype of the GABA_A 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 α₁ receptors were insensitive to diazepam.^[25] It would seem, then, that the anticonvulsant properties of clobazam are due to its selective affinity for ω₂.

In 1996, Nakamura et al. reported that clobazam and its active metabolite, N-desmethylclobazam (norclobazam), work by enhancing GABA-activated chloride currents at GABA_A-receptor-coupled Cl^- channels. 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.^[26]

Metabolism

Clobazam has two major metabolites: N-desmethyl-clobazam and 4'-hydroxyclobazam, the former of which is active.^[27] The demethylation is facilitated by CYP2C19, CYP3A4, and CYP2B6 and the 4'-hydroxyclobazam by CYP2C18 and CYP2C19.^[28]

Drug Interactions

• Alcohol increases bioavailability by 50%
• Cimetidine increases the effects of clobazam
• valproates

Overdose

See also: Benzodiazepine overdose

Benzodiazepines usually are not fatal when taken alone in overdose but those with underlying health conditions for example respiratory disease or when benzodiazepines are taken in combination with other CNS depressant drugs can result in death.^[29]

Abuse potential

See also: Benzodiazepine drug misuse

Clobazam in animal studies has been shown to increase reward seeking behaviours which may suggest an increased risk of addictive behavioural patterns.^[30] Significant clobazam abuse has been reported in some countries, according to a 1983 World Health Organisation report.^[31]

Chemistry

Weber, K. H.; Bauer, A.; Hauptmann, K. H.; Ann. 1972, 756, 128.

See also

• Benzodiazepine
• Benzodiazepine dependence
• Benzodiazepine withdrawal syndrome
• Long term effects of benzodiazepines

References

• Ochoa, Juan G. (2005). "GABA Receptor Agonists". Antiepileptic Drugs: An Overview. eMedicine.com, Inc. http://www.emedicine.com/neuro/topic692.htm#section~gaba_receptor_agonists. Retrieved 10 July 2005. 

End notes

1. ^ = 833759963&hitsperheading = on&infobase = pal_statutes.nfo&jd = a1975-116%2fsch.2-s.2&record = {49D05730}&softpage = DOC "MISUSE OF DRUGS ACT 1975". 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. Retrieved 28 September 2005. 
2. ^ ZA Patent 6800803
3. ^ Freche, C (1975). "Study of an anxiolytic, clobazam, in otorhinolaryngology in psychosomatic pharyngeal manifestations". Semaine des hopitaux. Therapeutique 51 (4): 261–3. PMID 5777. 
4. ^ "Clobazam in Treatment of Refractory Epilepsy: The Canadian Experience. A Retrospecti". Epilepsia 32 (3): 407–16. 1991. doi:10.1111/j.1528-1157.1991.tb04670.x. PMID 2044502. 
5. ^ Epilepsy Ontario (2005). "Clobazam". Medications. http://epilepsyontario.org/client/eo/EOWeb.nsf/web/clobazam. Retrieved 2006-03-04. 
6. ^ "Liste des médicaments contenant la substance: Clobazam". http://www.vidal.fr/substance/clobazam-1009.htm. Retrieved 2005-09-28. ^{[dead link]} Vidal.
7. ^ Larrieu, JL; Lagueny, A; Ferrer, X; Julien, J (1986). "Epilepsy with continuous discharges during slow-wave sleep. Treatment with clobazam". Revue d'electroencephalographie et de neurophysiologie clinique 16 (4): 383–94. PMID 3103177. 
8. ^ Gastaut, H; Tinuper, P; Aguglia, U; Lugaresi, E (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. PMID 6528075. 
9. ^ Biam Database (2001). "CLOBAZAM". Classes Chimiques: BENZODIAZEPINE. http://www.biam2.org/www/Sub1282.html. Retrieved 2005-09-28. 
10. ^ "Frisium Press Kit". Aventis Pharma India. Archived from the original on 2005-03-05. http://web.archive.org/web/20050305135005/http://www.aventispharmaindia.com/presskitsFrisium.htm. Retrieved 2006-08-02. 
11. ^ ^{a b} Nakajima, Hiroyuki (2001). "A pharmacological profile of clobazam (Mystan), a new antiepileptic drug". Folia Pharmacologica Japonica 118 (2): 117–22. doi:10.1254/fpj.118.117. PMID 11530681. 
12. ^ Shimizu, H; Kawasaki, J; Yuasa, S; Tarao, Y; Kumagai, S; Kanemoto, K (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. PMID 12810340. 
13. ^ Epilepsy New Zealand (2000). "Antiepileptic Medication". Archived from the original on 24 April 2005. http://web.archive.org/web/20050424183301/http://www.epilepsy.org.nz/sheets.cfm?SheetID=13&PageName=Antiepileptic+Medication. Retrieved 11 July 2005. 
14. ^ ^{a b c} sanofi-aventis (2002). "Frisium Tablets 10 mg, Summary of Product Characteristics from eMC". electronic Medicines Compendium. Medicines.org.uk. http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=8298. Retrieved 11 July 2005. 
15. ^ "FDA Approves ONFI™ (clobazam) for the Adjunctive Treatment of Seizures Associated with Lennox-Gastaut Syndrome in Patients Two Years and Older" (Press release). Lundbeck. http://www.lundbeckinc.com/USA/media/press-releases/2011/11_October_Onfi_Approval.asp. Retrieved 2011-10-25. 
16. ^ Isojärvi, JI; Tokola, RA (1998). "Benzodiazepines in the treatment of epilepsy in people with intellectual disability". Journal of intellectual disability research 42 (Suppl 1): 80–92. PMID 10030438. 
17. ^ Iwasaki, T; Miura, H; Sunaoshi, W; Hosoda, N; Takei, K; Katayama, F (2003). "A case of intractable epilepsy showing frequent gelastic seizures by administration of clobazam". No to hattatsu. Brain and development 35 (5): 406–10. PMID 13677950. 
18. ^ Monjanel-Mouterde, Suzanne; Antoni, Michel; Bun, Hot; Botta-Frindlund, Danielle; Gauthier, André; Durand, Alain; Cano, Jean Paul (1994). "Pharmacokinetics of a Single Oral Dose of Clobazam in Patients with Liver Disease". Pharmacology & Toxicology 74: 345–50. doi:10.1111/j.1600-0773.1994.tb01371.x. 
19. ^ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, A.A.; Vennat, B.; Llorca, P.-M. et al. (2009). "Benzodiazepine dependence: Focus on withdrawal syndrome". Annales Pharmaceutiques Françaises 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604. 
20. ^ Loiseau, P (1983). "Benzodiazepines in the treatment of epilepsy". L'Encephale 9 (4 Suppl 2): 287B–292B. PMID 6373234. 
21. ^ 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. PMID 3527689. 
22. ^ MacKinnon, Glenda L.; Parker, William A. (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. PMID 6133446. 
23. ^ Chweh, A; Swinyard, EA; Wolf, HH; Kupferberg, HJ (1985). "Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines". Life Sciences 36 (8): 737–44. doi:10.1016/0024-3205(85)90193-6. PMID 2983169. 
24. ^ Wildin, JD; Pleuvry, BJ; Mawer, GE; Onon, T; Millington, L (1990). "Respiratory and sedative effects of clobazam and clonazepam in volunteers". British journal of clinical pharmacology 29 (2): 169–77. PMC 1380080. PMID 2106335. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1380080. 
25. ^ McKernan, R. M.; Rosahl, T. W.; Reynolds, D. S.; Sur, C.; Wafford, K. A.; Atack, J. R.; Farrar, S.; Myers, J. et al. (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. PMID 10816315. 
26. ^ Nakamura, Fumihiro; Suzuki, Setsuo; Nishimura, Shigeko; Yagi, Kazuichi; Seino, Masakazu (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. PMID 8764810. 
27. ^ Contin, Manuela; Sangiorgi, Simonetta; Riva, Roberto; Parmeggiani, Antonia; Albani, Fiorenzo; Baruzzi, Agostino (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. PMID 12451290. 
28. ^ Cui, D.; Tran, A; Rey, E; Vincent, J; Tréluyer, JM; Pons, G (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. PMID 15483195. http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15483195. 
29. ^ Proenca, P; Teixeira, H; Pinheiro, J; Marques, E; Vieira, D (2004). "Forensic intoxication with clobazam: HPLC/DAD/MSD analysis". Forensic Science International 143 (2-3): 205–9. doi:10.1016/j.forsciint.2004.03.029. PMID 15240045. 
30. ^ Thiébot, Marie-Hélène; Bihan, Claudine; Soubrié, Philippe; Simon, Pierre (1985). "Benzodiazepines reduce the tolerance to reward delay in rats". Psychopharmacology 86 (1-2): 147–52. doi:10.1007/BF00431700. PMID 2862657. 
31. ^ WHO Review Group (1983). "Use and abuse of benzodiazepines". Bull World Health Organ (World Health Organisation) 61 (4): 551–562. PMC 2536139. PMID 6605211. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2536139. 

External links

• Inchem - Clobazam
• Mystan Prescribing Information Sheet (Japanese)