Clobazam

Clobazam
Names
Pronunciationkloe' ba zam[1]
Trade namesFrisium, Urbanol, Onfi, others[1]
IUPAC name
  • 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione
Clinical data
Drug classBenzodiazepine[1]
Main usesAnxiety, epilepsy[2]
Side effectsSedation, drooling, vomiting, constipation, pneumonia, poor coordination, appetite change[3]
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
    Routes of
    use    		By mouth
    Onset of action0.5–4 hours
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa612008
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • CA: Schedule IV
    • DE: Prescription only (Anlage III for higher doses)
    • NZ: Class C
    • UK: Class C
    • US: Schedule IV
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Bioavailability87% (by mouth)
    Protein binding80–90%
    MetabolismLiver
    Metabolites
      • N-desmethylclobazam
      • 4′-hydroxyclobazam
    Elimination half-life
      • clobazam: 36–42 hours
      • N-desmethylclobazam: 59–82 hours
    Excretion
    Chemical and physical data
    FormulaC16H13ClN2O2
    Molar mass300.74 g·mol−1
    3D model (JSmol)
    SMILES
    • ClC1=CC(N(C2=CC=CC=C2)C(CC(N3C)=O)=O)=C3C=C1
    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 checkY
    • Key:CXOXHMZGEKVPMT-UHFFFAOYSA-N checkY

    Clobazam, sold under the brand names Frisium among others, is a medication used to treat anxiety and epilepsy.[2] This includes Lennox-Gastaut and Dravet syndrome.[3] For anxiety it should only be used short term.[2] It is taken by mouth.[2]

    Common side effects include sedation, drooling, vomiting, constipation, pneumonia, poor coordination, and appetite change.[3] Other side effects may include misuse, suicide, Stevens-Johnson syndrome, and infertility.[3] Use during pregnancy may harm the baby.[3] It is a benzodiazepine that is believed to work by enhancing gamma-aminobutyric acid (GABA).[1]

    Clobazam was patented in 1968 and come into medical use in 1975.[4] It is available as a generic medication.[2] In the United Kingdom 30 pills of 10 mg costs the NHS about £4 as of 2021.[2] This amount in the United States is about 20 USD.[5] In the United States it is a schedule IV controlled substance.[3]

    Medical uses

    Clobazam is used for anxiety and epilepsy.

    Anxiety

    In the United Kingdom clobazam 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] Clobazam is also approved as a short-term (2–4 weeks) adjunctive agent in schizophrenia and other psychotic disorders to manage anxiety or agitation.[6]

    Seizures

    Clobazam is approved in Canada for add-on use in tonic-clonic, complex partial, and myoclonic seizures.[7] Clobazam is approved for adjunctive therapy in complex partial seizures,[8] certain types of status epilepticus, specifically the mycolonic, myoclonic-absent, simple partial, complex partial, and tonic varieties,[9] and non-status absence seizures.

    In India, clobazam is approved for use as an adjunctive therapy in epilepsy, and in acute and chronic anxiety.[10] In Japan, clobazam is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures.[11] In New Zealand, clobazam is marketed as Frisium[12] 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.[13]

    As an adjunctive therapy in epilepsy, it is used in people 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.[14] It is not recommended for use in children between the ages of six months and three years, unless there is a compelling need.[6]

    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.[15] 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.

    Dosage

    In adults it is often started at 20 to 30 mg per day, which may be increased to 60 mg per day.[2] Smaller doses should be used in older people.[2]

    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.[17]

    Side effects

    See also: Benzodiazepine dependence and Effects of long-term benzodiazepine use

    Common side effects include fever, drooling, and constipation.[18]

    Other side effects include hives and other rashes. In December 2013, the FDA added warnings to the label, that it can cause serious skin reactions, Stevens–Johnson syndrome, and toxic epidermal necrolysis, especially in the first eight weeks of treatment.[19]

    Abuse

    See also: Benzodiazepine use disorder

    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.[20]

    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.[21] Clobazam abuse has been reported in some countries, according to a 1983 World Health Organisation report.[22]

    Withdrawal

    In humans, tolerance to the anticonvulsant effects of clobazam may occur[23] and withdrawal seizures may occur during abrupt or overrapid withdrawal.[24]

    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.[25]

    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.[26]

    Interactions

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

    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.[27]

    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.[28][29]

    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.[30]

    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.[31]

    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,[32] creating a hyperpolarizing, inhibitory postsynaptic potential.[33] 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.[32]

    Metabolism

    Clobazam has two major metabolites: N-desmethylclobazam and 4′-hydroxyclobazam, the former of which is active.[34] The demethylation is facilitated by CYP2C19, CYP3A4, and CYP2B6 and the 4-hydroxyclobazam by CYP2C18 and CYP2C19.[35]

    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).[36]

    It is not soluble in water and is available in oral form only.[27][26]

    History

    Clobazam was discovered at the Maestretti Research Laboratories in Milan and was first published in 1969;[37] Maestretti was acquired by Roussel Uclaf[38] which became part of Sanofi.

    References

    1. 1 2 3 4 "Clobazam". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 2012. Archived from the original on 6 May 2021. Retrieved 5 January 2022.
    2. 1 2 3 4 5 6 7 8 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 355. ISBN 978-0857114105.
    3. 1 2 3 4 5 6 "Clobazam Monograph for Professionals". Drugs.com. Archived from the original on 23 November 2021. Retrieved 5 January 2022.
    4. ↑ "Clobazam (T3D4564)". Toxin and Toxin Target Database (T3DB. Archived from the original on 2020-11-25. Retrieved 2021-09-14.
    5. ↑ "Clobazam Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 5 January 2022.
    6. 1 2 3 sanofi-aventis (2002). "Frisium Tablets 10 mg, Summary of Product Characteristics from eMC". electronic Medicines Compendium. Medicines.org.uk. Archived from the original on 6 December 2007. Retrieved 11 July 2005.
    7. ↑ "Clobazam". Epilepsy Ontario. 2020. Archived from the original on 2020-02-04. Retrieved 2020-08-21.
    8. ↑ 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 français). 16 (4): 383–94. doi:10.1016/S0370-4475(86)80028-4. PMID 3103177.
    9. ↑ 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. PMID 6528075.
    10. ↑ "Frisium Press Kit". Aventis Pharma India. Archived from the original on 2005-03-05. Retrieved 2006-08-02.
    11. ↑ 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. PMID 12810340.
    12. ↑ Epilepsy New Zealand (2000). "Antiepileptic Medication". Archived from the original on 11 March 2005. Retrieved 11 July 2005.
    13. ↑ "FDA Approves ONFI™ (clobazam) for the Adjunctive Treatment of Seizures Associated with Lennox-Gastaut Syndrome in Patients Two Years and Older" (Press release). Lundbeck. Archived from the original on 2011-10-27. Retrieved 2011-10-25.
    14. ↑ Arya R, Giridharan N, Anand V, Garg SK (July 2018). "Clobazam monotherapy for focal or generalized seizures". The Cochrane Database of Systematic Reviews. 7: CD009258. doi:10.1002/14651858.CD009258.pub3. PMC 6513499. PMID 29995989.
    15. ↑ 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 (Suppl 1): 80–92. PMID 10030438.
    16. ↑ Monjanel-Mouterde S, Antoni M, Bun H, Botta-Frindlund D, Gauthier A, Durand A, Cano JP (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. PMID 7937568.
    17. ↑ 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. PMID 19900604.
    18. ↑ "Clobazam label" (PDF). December 2014. Archived (PDF) from the original on 2021-04-05. Retrieved 2021-09-14.
    19. ↑ 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 Archived 2017-07-22 at the Wayback Machine
    20. ↑ "FDA expands Boxed Warning to improve safe use of benzodiazepine drug". U.S. Food and Drug Administration (FDA). 23 September 2020. Archived from the original on 24 September 2020. Retrieved 23 September 2020. Public Domain This article incorporates text from this source, which is in the public domain.
    21. ↑ 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. PMID 2862657. S2CID 30614502.
    22. ↑ WHO Review Group (1983). "Use and abuse of benzodiazepines". Bulletin of the World Health Organization. 61 (4): 551–62. PMC 2536139. PMID 6605211.
    23. ↑ Loiseau P (1983). "[Benzodiazepines in the treatment of epilepsy]". L'Encephale. 9 (4 Suppl 2): 287B–292B. PMID 6373234.
    24. ↑ 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. PMID 3527689. S2CID 23166797.
    25. ↑ 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. PMID 6133446.
    26. 1 2 Fruchtengarten L Inchem - Clobazam Archived 2018-11-12 at the Wayback Machine. Created July 1997, Reviewed 1998.
    27. 1 2 Ochoa JG (2005). "Antiepileptic Drugs: An Overview. GABA Receptor Agonists". Drugs and Diseases. Medccape. Archived from the original on 15 December 2008. Retrieved 10 July 2005.
    28. ↑ 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. PMC 4981430. PMID 27392635.
    29. ↑ 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. PMID 11530681.
    30. ↑ 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. PMC 1380080. PMID 2106335.
    31. ↑ 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. PMID 10816315. S2CID 10340592.
    32. 1 2 Nakamura 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. PMID 8764810. S2CID 12628361.
    33. ↑ 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. PMC 6585772. PMID 30285275.
    34. ↑ 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. PMID 12451290. S2CID 44444755.
    35. ↑ 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. PMID 15483195.
    36. ↑ 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. PMID 19298435. S2CID 20445985.
    37. ↑ 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. PMC 1429523. PMID 35198.
    38. ↑ Zirulia G (2014). L'industria delle Medicine. EDRA LSWR. ISBN 9788821439049. Archived from the original on 2021-11-02. Retrieved 2021-09-14.
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