Open Access Articles- Top Results for Clobazam


Systematic (IUPAC) name
Clinical data
Trade names Frisium, Urbanol, Onfi
AHFS/ Micromedex Detailed Consumer Information
Licence data US FDA:link
  • US: C (Risk not ruled out)
Pharmacokinetic data
Bioavailability 90%
Protein binding 83%
Metabolism Hepatic
Half-life 18 h
Excretion Renal
22316-47-8 7pxY
PubChem CID 2789
DrugBank DB00349 7pxY
ChemSpider 2687 7pxY
UNII 2MRO291B4U 7pxY
KEGG D01253 7pxY
ChEBI CHEBI:31413 7pxY
Chemical data
Formula C16H13ClN2O2
 14pxY (what is this?)  (verify)

Clobazam (marketed under the brand names Frisium, Urbanol and Onfi) is a benzodiazepine derivative that has been marketed as an anxiolytic since 1975[2] and an anticonvulsant since 1984.[3]

Medical uses

Clobazam is usually used for epilepsy. It is unclear if there are any benefits to clobazam over other seizure medications for children with Rolandic epilepsy.[4]

As of 2005, clobazam is approved in Canada for add-on use in tonic-clonic, complex partial, and myoclonic seizures.[5] Clobazam is approved for adjunctive therapy in complex partial seizures[6] certain types of status epilepticus, specifically the myoclonic, myoclonic-absent, simple partial, complex partial, and tonic varieties,[7] and non-status absence seizures. It is also approved for treatment of anxiety. In India, clobazam is approved for use as an adjunctive therapy in epilepsy and in acute and chronic anxiety.[8] In Japan, clobazam is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures.[9] In New Zealand, clobazam is marketed as Frisium[10] 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.[11] 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.[12]

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.[11] 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.[11]

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.[13] 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.


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

Side effects




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

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.[17]

Tolerance and dependence

In humans tolerance to the anticonvulsant effects of clobazam frequently occurs[18] and withdrawal seizures can occur during abrupt or overrapid withdrawal.[19]

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.[20]


Clobazam is an anticonvulsant.[21] 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 GABAA receptor compared to the 1,4-benzodiazepines. It has selective affinity for the ω2 site, where it has agonistic activity.[22]

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.[23]

The ω1-receptor, which is found on the α1 subtype of the GABAA 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.[24] 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 GABAA-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.[25]


Clobazam has two major metabolites: N-desmethyl-clobazam and 4'-hydroxyclobazam, the former of which is active.[26] The demethylation is facilitated by CYP2C19, CYP3A4, and CYP2B6 and the 4'-hydroxyclobazam by CYP2C18 and CYP2C19.[27]

Drug Interactions


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.[28]

Abuse potential

Clobazam in animal studies has been shown to increase reward seeking behaviours which may suggest an increased risk of addictive behavioural patterns.[29] Significant clobazam abuse has been reported in some countries, according to a 1983 World Health Organisation report.[30]


Clobazam synthesis:[31]

Acylation of the nitrodiphenylamine with ethyl malonyl chloride gives the corresponding amido-ester. The nitro group is then reduced to the amine by catalytic hydrogenation to give the intermediate. Reaction of that with a strong base closes the benzodiazepine ring. Methylation of the secondary aniline by means of methyl iodide completes the synthesis of clobazam.

See also


  • Ochoa, Juan G. (2005). "GABA Receptor Agonists". Antiepileptic Drugs: An Overview., Inc. 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". Retrieved 28 September 2005. 
  2. ^ Freche, C (1975). "Study of an anxiolytic, clobazam, in otorhinolaryngology in psychosomatic pharyngeal manifestations". Semaine des Hôpitaux. Thérapeutique 51 (4): 261–3. PMID 5777. 
  3. ^ "Clobazam in Treatment of Refractory Epilepsy: The Canadian Experience. A Retrospecti". Epilepsia 32 (3): 407–16. 1991. PMID 2044502. doi:10.1111/j.1528-1157.1991.tb04670.x. 
  4. ^ Arya, R; Anand, V; Garg, SK; Michael, BD (Oct 4, 2014). "Clobazam monotherapy for partial-onset or generalized-onset seizures.". The Cochrane database of systematic reviews 10: CD009258. PMID 25280512. doi:10.1002/14651858.CD009258.pub2. 
  5. ^ Epilepsy Ontario (2005). "Clobazam". Medications. Retrieved 2006-03-04. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ "Frisium Press Kit". Aventis Pharma India. Archived from the original on 2005-03-05. Retrieved 2006-08-02. 
  9. ^ 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. PMID 12810340. doi:10.1016/S1059-1311(02)00287-X. 
  10. ^ Epilepsy New Zealand (2000). "Antiepileptic Medication". Archived from the original on 24 April 2005. Retrieved 11 July 2005. 
  11. ^ a b c sanofi-aventis (2002). "Frisium Tablets 10 mg, Summary of Product Characteristics from eMC". electronic Medicines Compendium. Retrieved 11 July 2005. 
  12. ^ "FDA Approves ONFI™ (clobazam) for the Adjunctive Treatment of Seizures Associated with Lennox-Gastaut Syndrome in Patients Two Years and Older" (Press release). Lundbeck. Retrieved 2011-10-25. 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ a b
  16. ^ 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 (4–5): 345–50. doi:10.1111/j.1600-0773.1994.tb01371.x. 
  17. ^ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, A.A.; Vennat, B.; Llorca, P.-M.; Eschalier, A. (2009). "Benzodiazepine dependence: Focus on withdrawal syndrome". Annales Pharmaceutiques Françaises 67 (6): 408–13. PMID 19900604. doi:10.1016/j.pharma.2009.07.001. 
  18. ^ Loiseau, P (1983). "Benzodiazepines in the treatment of epilepsy". L'Encephale 9 (4 Suppl 2): 287B–292B. PMID 6373234. 
  19. ^ 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. doi:10.1111/j.1528-1157.1986.tb05730.x. 
  20. ^ 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. PMID 6133446. doi:10.3109/00952998209002608. 
  21. ^ 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. PMID 2983169. doi:10.1016/0024-3205(85)90193-6. 
  22. ^ Nakajima, Hiroyuki (2001). "A pharmacological profile of clobazam (Mystan), a new antiepileptic drug". Folia Pharmacologica Japonica 118 (2): 117–22. PMID 11530681. doi:10.1254/fpj.118.117. 
  23. ^ 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. doi:10.1111/j.1365-2125.1990.tb03616.x. 
  24. ^ 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. PMID 10816315. doi:10.1038/75761. 
  25. ^ 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. PMID 8764810. doi:10.1111/j.1528-1157.1996.tb00643.x. 
  26. ^ 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. PMID 12451290. doi:10.1097/00007691-200212000-00009. 
  27. ^ 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. PMID 15483195. doi:10.1124/dmd.32.11.1279 (inactive 2015-01-11). 
  28. ^ 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. PMID 15240045. doi:10.1016/j.forsciint.2004.03.029. 
  29. ^ 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. PMID 2862657. doi:10.1007/BF00431700. 
  30. ^ WHO Review Group (1983). "Use and abuse of benzodiazepines". Bull World Health Organ (World Health Organisation) 61 (4): 551–562. PMC 2536139. PMID 6605211. 
  31. ^ Weber, K. H.; Bauer, A.; Hauptmann, K. H. (1972). "Benzodiazepine mit psychotroper Wirkung, III.N-Aryl- undN-Heteroaryl-1H-1.5-benzodiazepin-2.4-[3H.5H]-dione". Justus Liebigs Annalen der Chemie 756: 128. doi:10.1002/jlac.19727560112.  edit

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