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Clobazam

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Clobazam
Clinical data
Trade namesOnfi, Frisium, Urbanyl, others[1][2]
Other namesClobazepam
AHFS/Drugs.comMonograph
MedlinePlusa612008
License data
Pregnancy
category
  • AU: C
Dependence
liability		High
Addiction
liability		High
Routes of
administration		By mouth, sublingual
Drug classBenzodiazepine, Anticonvulsant
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityRapidly and extensively absorbed; 87%–95% (oral)[6]
Protein binding80–90%
MetabolismLiver
Metabolites
    • • N-desmethylclobazam
      (norclobazam, 4-oxo-lofendazam)[7]
    • • 9-Hydroxy-N-desmethylclobazam
      [8][9]
    • • 4'-Hydroxy-N-desmethylclobazam
    • • 4'-Hydroxyclobazam[10]
Onset of action0.5–4 hours[11]
Elimination half-life
    • • clobazam: 36–42 hours
    • N-desmethylclobazam: 71–82 hours
[12]
Excretion
Identifiers
  • 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.040.810 Edit this at Wikidata
Chemical and physical data
FormulaC16H13ClN2O2
Molar mass300.74 g·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,10H2,1H3
  • Key:CXOXHMZGEKVPMT-UHFFFAOYSA-N

Clobazam (INN) is a long-acting benzodiazepine derivative sold under the brand name Frisium among others, is primarily used as an anticonvulsant and anxiolytic.[13] Clobazam is a 1,5-benzodiazepine with unique pharmacological characteristics that was patented in 1968.[14][15] Clobazam was first synthesized in 1966 and first published in 1969. The primary drug development goal was to provide greater anti-anxiety and anti-obsessive efficacy with fewer benzodiazepine-related side effects.[16] It was approved in Australia (Frisium) in 1970 and France (Urbanyl) in 1974 for short-term anxiety management.[16][17][18] Marketing for clobazam in the treatment of epilepsy began in 1984.[19] Clobazam is used in the United States only as an anticonvulsant in the treatment of epilepsy, but is available in other countries as an anti-anxiety agent for the short-term treatment of acute and disabling anxiety. It has shown a distinct profile and addictive potential compared to the more common benzodiazepines.[20] Clobazam is the only 1,5‑benzodiazepine that has been marketed for clinical use, making it the sole representative of this structural class of benzodiazepines.

In 2005, clobazam also received approval from Health Canada as an add-on therapy for generalized tonic–clonic, myoclonic, and focal impaired awareness seizures.[21] On October 21, 2011, clobazam was approved by the United States Food and Drug Administration. Lundbeck marketed clobazam under the brand name Onfi as an adjunctive treatment for seizures associated with Lennox–Gastaut syndrome in adults and children aged two years of age and older.

Medical uses

[edit]
Frisium (clobazam) 10 mg tablet blister pack

Clobazam (also known as clobazepam) is a 1,5-benzodiazepine derivative primarily used as an anticonvulsant for adjunctive therapy in epilepsy and used as an anti-anxiety agent for short-term relief of severe and disabling anxiety. Benzodiazepines are central nervous system (CNS) depressants and work by enhancing the effects of gamma-Aminobutyric acid (GABA). The increased GABA inhibition on the neural systems, throughout the central nervous system in turn reducing neuronal excitability throughout the nervous system. Clobazam is rapidly and almost completely absorbed following oral administration. It acts quickly, maintaining a therapeutic effect for a long duration.

Clobazam is also sometimes used for sedation for preoperational anxiety.

Clobazam is sometimes used for refractory epilepsies. However, long-term prophylactic treatment of epilepsy may have considerable drawbacks, most importantly decreased anti-epileptic effects due to drug tolerance which may render long-term therapy less effective.[22] Other anti-epileptic 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 causing benzodiazepine withdrawal syndrome.

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.[23] It is not recommended for use in children between the ages of six months and three years, unless there is a compelling need.[24] In the United Kingdom in addition to epilepsy and severe anxiety, clobazam (Frisium) is approved for a short-term (2–4 weeks) adjunctive agent in schizophrenia and other psychotic disorders to manage anxiety or agitation.[24][25] In the United Kingdom clobazam is also 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.[24]

Clobazam is approved in Canada (Frisium) for add-on use in tonic-clonic, complex partial, and myoclonic seizures.[26] Clobazam is approved for adjunctive therapy in complex partial seizures,[27] certain types of status epilepticus, specifically the myoclonic, myoclonic-absent, simple partial, complex partial, and tonic varieties,[28] and non-status absence seizures. It is also approved for the treatment of anxiety.

In India, clobazam (Clobaday) is approved for adjunctive therapy in epilepsy and in acute and chronic anxiety.[29] In Japan, clobazam (Mystan) is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures.[30] In New Zealand, clobazam is marketed as Frisium.[31]

In the United States, clobazam (Onfi) was not marketed until October 2011 and only approved as an anticonvulsant. Clobazam is indicated for use in combination with other medicines to control epilepsy in people aged two years of age and older who have a specific severe form of epilepsy called Lennox–Gastaut syndrome.[5][32]

Clinical efficacy and tolerability for management of chronic epilepsy and anxiety disorders has been established in multiple studies.[33]

Side effects

[edit]

In September 2020, the US Food and Drug Administration 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.[34]

Common

[edit]

Common side effects include sedation, drooling, constipation, headaches, trembling hands, digestive problems, low blood pressure, dry mouth, nausea, addiction, physical and psychological dependence.[5]

Warnings and precautions

[edit]

In December 2013, the US Food and Drug Administration 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.[35]

• Prescription Only: Clobazam requires a doctor's prescription. When prescribing clobazam, a controlled substance, doctors must adhere to strict legal and clinical protocols.

• Severe Interactions: Taking it with opioids, alcohol, or other CNS depressants can lead to extreme drowsiness, slowed or stopped breathing, coma, and death.[36]

• Abuse and Dependence: Clobazam is a benzodiazepine derivative, it is a habit-forming controlled substance with a risk for misuse, abuse, addiction and physical dependence.[37]

• Withdrawal: Never stop taking clobazam abruptly. Sudden discontinuation can cause life-threatening withdrawal seizures and severe reactions. Dosages must be tapered down slowly under the direct supervision of a healthcare provider.[38]

Overdose

[edit]

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.[39]

Abuse potential and addiction

[edit]
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.[40] Clobazam abuse has been reported in some countries, according to a 1983 World Health Organization report.[41]

Dependence and withdrawal

[edit]

In humans, tolerance to the anticonvulsant effects of clobazam may occur[42] and withdrawal seizures may occur during abrupt or over-rapid withdrawal.[43]

Clobazam as with other benzodiazepine drugs can lead to physical dependence, addiction, and what is known as 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.[44]

Pharmacology

[edit]
Structure of
N-desmethylclobazam
(norclobazam, 4-oxo-lofendazam)

Clobazam is predominantly a positive allosteric modulator at the GABAA receptor to increase GABAergic transmission, particularly chloride conductance in neurons and with some speculated additional activity at sodium channels and voltage-sensitive calcium channels.[45] Clobazam binds at a distinct binding site associated with a Cl− ionophore at the GABAA receptor, increasing the duration of time for which the Cl− ionophore is open. The post-synaptic inhibitory effect of GABA in the thalamus is prolonged as a result.[46]

The exact mechanism of action for clobazam, a 1,5-benzodiazepine, which has anticonvulsant and anxiolytic effects similar to those produced by other benzodiazepine derivatives. Clobazam is a potent partial agonist at the GABAA receptor and the effects are related to binding to one or more specific GABA receptor subunits, increasing GABA-mediated inhibition. Clobazam is thought to involve the potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABAA receptor. Like other 1,5-benzodiazepines (for example, arfendazam, lofendazam, triflubazam, and CP-1414S), clobazam and the active metabolite N-desmethylclobazam have less affinity for the α1 subunit (sedative effects) of the GABAA receptor compared to the 1,4-benzodiazepines. They have a higher affinity for the α2 subunit (anxiolytic effects) and γ2 subunit of the GABAA receptor, which is essential for the anticonvulsant and anxiolytic effects of clobazam.[47][48] It is generally considered less sedating and causes less tolerance than traditional 1,4-benzodiazepines, partially because it binds less to subunits that cause sedation.

N-desmethylclobazam, is the active metabolite of the benzodiazepine, clobazam. It works by enhancing GABA-activated chloride influx at GABAA receptor,[49] creating a hyperpolarizing, inhibitory postsynaptic potential.[50] The primary active metabolite N-desmethylclobazam, circulates at higher levels than the parent drug at therapeutic dosages. Plasma concentrations of N-desmethylclobazam are approximately 3–5 times higher than those of clobazam.[51] The primary active metabolite of clobazam, is crucial for its prolonged anti-epileptic and anti-anxiety effects, acting similarly on GABAA receptors but with potentially greater importance in long-term therapy, especially for epilepsy, and is largely responsible for the drug's overall clinical action. 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.[49]

Metabolism

[edit]

Clobazam has four major metabolites: N-desmethylclobazam, 4'-Hydroxy-N-desmethylclobazam, the former of which is active[52] and 4'-Hydroxyclobazam[10] The demethylation is facilitated by CYP2C19, CYP3A4, and CYP2B6 and the 4'-Hydroxyclobazam by CYP2C18 and CYP2C19.[53] N-desmethylclobazam is further metabolized and cleared through hydroxylation by the enzyme CYP2C19. 9-Hydroxy-N-desmethylclobazam is one of the hydroxylated products of this process. While the parent drug clobazam is highly active, its primary metabolite, N-desmethylclobazam, is also pharmacologically active and possesses a significantly longer half-life (compared to clobazam's 36–42 hours). 9-Hydroxy-N-desmethylclobazam functions mostly as a pathway toward drug clearance.[54]

The half-life is approximately 36 to 42 hours for clobazam and 71 to 82 hours for N-desmethylclobazam.[55]

Chemistry

[edit]
Synthesis of clobazam

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).[56]

History

[edit]

Clobazam was discovered at the Maestretti Research Laboratories in Milan and was first published in 1969.[57] Maestretti was acquired by Roussel Uclaf[58] which became part of Sanofi.

Society and culture

[edit]
[edit]

Internationally clobazam is a federally controlled Schedule IV Psychotropic Substance with potential for abuse, addiction, and severe withdrawal if stopped abruptly.

Brand names for Clobazam

[edit]

Onfi: Available as oral tablets in 10 mg and 20mg and an oral suspension. The liquid comes in a 2.5-mg/mL strength with a berry flavor. (United States)
Sympazan: Available as 5 mg, 10 mg, 20 mg berry-flavored sublingual films that dissolve in the mouth. (United States)
Frisium: 5 mg, 10 mg, 20 mg tablets (Global, Europe, Australia, Canada, United Kingdom, New Zealand)
Urbanol: 5 mg capsules and 10 mg tablets (Common in South Africa)
Urbanyl: 5 mg, 10 mg, 20 mg (Used in France and other regions)
Mystan: 5 mg, 10 mg, 20 mg tablets (Distributed in Japan)
Clobaday: 5 mg, 10 mg, 20 mg tablets (Distributed in India)
Epaclob: clobazam oral suspension 5mg/5ml and 10mg/5ml in France, Ireland, Germany, and Italy.
Silocalm: clobazam oral suspension 5mg/5ml and 10mg/5ml in Denmark, Spain, and Iceland.

See also

[edit]

References

[edit]
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Further reading

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Retrieved from "https://en.wikipedia.org/w/index.php?title=Clobazam&oldid=1356952999"