Chemistry:Clobazam

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Short description: Benzodiazepine class medication
Clobazam
Clobazam structure.svg
Clobazam ball-and-stick model.png
Clinical data
Trade namesFrisium, Urbanol, Onfi, others
AHFS/Drugs.comMonograph
MedlinePlusa612008
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
administration		By mouth
Drug classBenzodiazepine
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability87% (oral)
Protein binding80–90%
MetabolismLiver
Metabolites
    • N-desmethylclobazam
    • 4′-hydroxyclobazam
Onset of action0.5–4 hours
Elimination half-life
    • clobazam: 36–42 hours
    • N-desmethylclobazam: 59–82 hours
Excretion
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC16H13ClN2O2
Molar mass300.74 g·mol−1
3D model (JSmol)
  (verify)

Clobazam, sold under the brand names Frisium, Onfi and others, is a benzodiazepine class medication that was patented in 1968.[1] Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxioselective anxiolytic since 1970,[2][3] and an anticonvulsant since 1984.[4] The primary drug-development goal was to provide greater anxiolytic, anti-obsessive efficacy with fewer benzodiazepine-related side effects.[2]

Medical uses

Clobazam is used for its anxiolytic effect, and as an adjunctive therapy in epilepsy.

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 with Rolandic epilepsy or other epileptic syndromes.[5] It is not recommended for use in children between the ages of six months and three years, unless there is a compelling need.[6] In addition to epilepsy and severe anxiety, clobazam it is approved in United Kingdom as a short-term (2–4 weeks) adjunctive agent in schizophrenia and other psychotic disorders to manage anxiety or agitation.[6][7]

Clobazam is sometimes used for refractory epilepsies. However, long-term prophylactic treatment of epilepsy may have considerable drawbacks, most importantly decreased antiepileptic effects due to drug tolerance which may render long-term therapy less effective.[8] 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 the benzodiazepine withdrawal syndrome.

Clobazam is approved in Canada for add-on use in tonic-clonic, complex partial, and myoclonic seizures.[9] Clobazam is approved for adjunctive therapy in complex partial seizures,[10] certain types of status epilepticus, specifically the myoclonic, myoclonic-absent, simple partial, complex partial, and tonic varieties,[11] and non-status absence 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 chronic anxiety.[12] In Japan, clobazam is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures.[13] In New Zealand, clobazam is marketed as Frisium[14] 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.[6] It was not approved in the United States until October 25, 2011, when it was approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older.[15]

The current FDA indicated 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[16] and it is available in multiple formulations under the brand names Onfi and Sympazan as well as generic formulations.

Contraindications

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 with comorbid psychiatric disorders.[18]

Side 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.[19]

Common

Common side effects include fever, drooling, and constipation.[20]

Post-marketing experience

Warnings and precautions

In December 2013, the FDA added warnings to the label for clobazam, that it can cause serious skin reactions, Stevens–Johnson syndrome, and toxic epidermal necrolysis, especially in the first eight weeks of treatment.[21]

Drug interactions

  • Alcohol increases bioavailability by 50%; compounded depressant effect may precipitate life-threatening toxicity.
  • Cimetidine increases the effects of clobazam.
  • Valproate.

Overdose

Overdose and intoxication with benzodiazepines, including clobazam, may lead to CNS depression, associated with drowsiness, confusion, and lethargy, possibly progressing to ataxia, 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.[22]

Abuse potential and addiction

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.[23] Clobazam abuse has been reported in some countries, according to a 1983 World Health Organisation report.[24]

Dependence and withdrawal

In humans, tolerance to the anticonvulsant effects of clobazam may occur[25] and withdrawal seizures may occur during abrupt or over-rapid withdrawal.[26]

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 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.[27]

Pharmacology

Clobazam is predominantly a positive allosteric modulator at the GABAA receptor with some speculated additional activity at sodium channels and voltage-sensitive calcium channels.[28]

Like other 1,5-benzodiazepines (for example, arfendazam, lofendazam, or CP-1414S), the active metabolite N-desmethylclobazam has less affinity for the α1 subunit of the GABAA receptor compared to the 1,4-benzodiazepines. It has higher affinity for α2 containing receptors, where it has positive modulatory activity.[29][30]

In a double-blind placebo-controlled trial published in 1990 comparing it to clonazepam, 10 mg of clobazam was shown to be less sedative than either 0.5 mg or 1 mg of clonazepam.[31]

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.[32]

In 1996, Nakamura et al. reported that clobazam and its active metabolite, N-desmethylclobazam (norclobazam), work by enhancing GABA-activated chloride influx at GABAA receptors,[33] creating a hyperpolarizing, inhibitory postsynaptic potential.[34] It was also reported that these effects were inhibited by the GABA antagonist flumazenil, and that clobazam acts more efficiently in GABA-deficient brain tissue.[33]

Metabolism

Clobazam has two major metabolites: N-desmethylclobazam and 4′-hydroxyclobazam, the former of which is active.[35] The demethylation is facilitated by CYP2C19, CYP3A4, and CYP2B6 and the 4-hydroxyclobazam by CYP2C18 and CYP2C19.[36]

In children, clobazam half-life values is average 16 hours, while in the elderly, clobazam half-life values are 30 to 48 hours.[37][38]

Chemistry

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).[39]

It is not soluble in water and is available in oral form only.[28][22]

History

Clobazam was discovered at the Maestretti Research Laboratories in Milan and was first published in 1969;[40] Maestretti was acquired by Roussel Uclaf[41] which became part of Sanofi.

See also

References

  1. ↑ "Clobazam (T3D4564)". Toxin and Toxin Target Database (T3DB. http://www.t3db.ca/toxins/T3D4564. 
  2. ↑ 2.0 2.1 "Clobazam". StatPearls. Treasure Island (FL): StatPearls Publishing. 2020. 
  3. ↑ "[Study of an anxiolytic, clobazam, in otorhinolaryngology in psychosomatic pharyngeal manifestations]". Semaine des Hopitaux. Therapeutique 51 (4): 261–3. April 1975. PMID 5777. 
  4. ↑ "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. PMID 2044502. 
  5. ↑ "Clobazam monotherapy for focal or generalized seizures". The Cochrane Database of Systematic Reviews 2018 (7): CD009258. July 2018. doi:10.1002/14651858.CD009258.pub3. PMID 29995989. 
  6. ↑ 6.0 6.1 6.2 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. 
  7. ↑ "Clobazam 10 mg Tablets - Summary of Product Characteristics (SmPC) - (emc)". https://www.medicines.org.uk/emc/product/15103/smpc. 
  8. ↑ "Benzodiazepines in the treatment of epilepsy in people with intellectual disability". Journal of Intellectual Disability Research 42 (Suppl 1): 80–92. December 1998. PMID 10030438. 
  9. ↑ "Clobazam". Epilepsy Ontario. 2020. https://epilepsyontario.org/about-epilepsy/treatments/medications/clobazam/. 
  10. ↑ "[Epilepsy with continuous discharges during slow-wave sleep. Treatment with clobazam]" (in fr). Revue d'Electroencephalographie et de Neurophysiologie Clinique 16 (4): 383–94. December 1986. doi:10.1016/S0370-4475(86)80028-4. PMID 3103177. 
  11. ↑ "[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. December 1984. doi:10.1016/S0370-4475(84)80005-2. PMID 6528075. 
  12. ↑ "Frisium Press Kit". Aventis Pharma India. http://www.aventispharmaindia.com/presskitsFrisium.htm. 
  13. ↑ "Use of clobazam for the treatment of refractory complex partial seizures". Seizure 12 (5): 282–6. July 2003. doi:10.1016/S1059-1311(02)00287-X. PMID 12810340. 
  14. ↑ Epilepsy New Zealand (2000). "Antiepileptic Medication". http://www.epilepsy.org.nz/sheets.cfm?SheetID=13&PageName=Antiepileptic%20Medication. 
  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. Retrieved 2011-10-25.
  16. ↑ SYMPAZAN: HIGHLIGHTS OF PRESCRIBING INFORMATION, FDA.
  17. ↑ "Pharmacokinetics of a single oral dose of clobazam in patients with liver disease". Pharmacology & Toxicology 74 (6): 345–50. June 1994. doi:10.1111/j.1600-0773.1994.tb01371.x. PMID 7937568. 
  18. ↑ "Benzodiazepine dependence: focus on withdrawal syndrome". Annales Pharmaceutiques Françaises 67 (6): 408–13. November 2009. doi:10.1016/j.pharma.2009.07.001. PMID 19900604. 
  19. ↑ "FDA expands Boxed Warning to improve safe use of benzodiazepine drug". 23 September 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class.  This article incorporates text from this source, which is in the public domain.
  20. ↑ "Clobazam label". December 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202067s003,203993s003lbl.pdf. 
  21. ↑ FDA. December 3rd, 2013 FDA Drug Safety Podcast: FDA warns of serious skin reactions with the anti-seizure drug Onfi (clobazam) and has approved label changes
  22. ↑ 22.0 22.1 Fruchtengarten L Inchem - Clobazam. Created July 1997, Reviewed 1998.
  23. ↑ "Benzodiazepines reduce the tolerance to reward delay in rats". Psychopharmacology 86 (1–2): 147–52. 1985. doi:10.1007/BF00431700. PMID 2862657. 
  24. ↑ WHO Review Group (1983). "Use and abuse of benzodiazepines". Bulletin of the World Health Organization 61 (4): 551–62. PMID 6605211. 
  25. ↑ "[Benzodiazepines in the treatment of epilepsy]". L'Encéphale 9 (4 Suppl 2): 287B–292B. 1983. PMID 6373234. 
  26. ↑ "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. 1986. doi:10.1111/j.1528-1157.1986.tb05730.x. PMID 3527689. 
  27. ↑ "Benzodiazepine withdrawal syndrome: a literature review and evaluation". The American Journal of Drug and Alcohol Abuse 9 (1): 19–33. 1982. doi:10.3109/00952998209002608. PMID 6133446. 
  28. ↑ 28.0 28.1 "Antiepileptic Drugs: An Overview. GABA Receptor Agonists". Drugs and Diseases. Medccape. 2005. http://emedicine.medscape.com/article/1187334-overview#a4. 
  29. ↑ "The clobazam metabolite N-desmethyl clobazam is an α2 preferring benzodiazepine with an improved therapeutic window for antihyperalgesia". Neuropharmacology 109: 366–375. October 2016. doi:10.1016/j.neuropharm.2016.07.004. PMID 27392635. 
  30. ↑ "[A pharmacological profile of clobazam (Mystan), a new antiepileptic drug]". Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica 118 (2): 117–22. August 2001. doi:10.1254/fpj.118.117. PMID 11530681. 
  31. ↑ "Respiratory and sedative effects of clobazam and clonazepam in volunteers". British Journal of Clinical Pharmacology 29 (2): 169–77. February 1990. doi:10.1111/j.1365-2125.1990.tb03616.x. PMID 2106335. 
  32. ↑ "Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype". Nature Neuroscience 3 (6): 587–92. June 2000. doi:10.1038/75761. PMID 10816315. 
  33. ↑ 33.0 33.1 "Effects of clobazam and its active metabolite on GABA-activated currents in rat cerebral neurons in culture". Epilepsia 37 (8): 728–35. August 1996. doi:10.1111/j.1528-1157.1996.tb00643.x. PMID 8764810. 
  34. ↑ "A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam". Journal of Clinical Pharmacology 59 (1): 7–19. January 2019. doi:10.1002/jcph.1313. PMID 30285275. 
  35. ↑ "Evidence of polymorphic CYP2C19 involvement in the human metabolism of N-desmethylclobazam". Therapeutic Drug Monitoring 24 (6): 737–41. December 2002. doi:10.1097/00007691-200212000-00009. PMID 12451290. 
  36. ↑ "In vitro characterization of clobazam metabolism by recombinant cytochrome P450 enzymes: importance of CYP2C19". Drug Metabolism and Disposition 32 (11): 1279–86. November 2004. doi:10.1124/dmd.32.11.1279. PMID 15483195. 
  37. ↑ Patsalos, Philip N. (2022), Patsalos, Philip N., ed., "Clobazam" (in en), Antiseizure Medication Interactions: A Clinical Guide (Cham: Springer International Publishing): pp. 55–59, doi:10.1007/978-3-030-82790-8_7, ISBN 978-3-030-82790-8, https://doi.org/10.1007/978-3-030-82790-8_7, retrieved 2024-01-19 
  38. ↑ Ng, Yu-tze; Collins, Stephen D. (2007-01-01). "Clobazam". Neurotherapeutics. New Antiepileptic Drugs: Discovery, Development, and Update 4 (1): 138–144. doi:10.1016/j.nurt.2006.11.002. ISSN 1878-7479. PMID 17199029. 
  39. ↑ "Drug treatment of epilepsy in the century of the ILAE: the second 50 years, 1959-2009". Epilepsia 50 (Suppl 3): 93–130. March 2009. doi:10.1111/j.1528-1167.2009.02042.x. PMID 19298435. 
  40. ↑ "Clobazam: pharmacological and therapeutic profile". British Journal of Clinical Pharmacology 7 (Suppl 1): 151S–155S. 1979. doi:10.1111/j.1365-2125.1979.tb04685.x. PMID 35198. 
  41. ↑ Zirulia, Giuliano (2014). L'industria delle Medicine.. EDRA LSWR. ISBN 9788821439049. https://books.google.com/books?id=KuglCgAAQBAJ&q=Maestretti+&pg=PT195. 

Further reading

External links



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