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| Clinical data | |
|---|---|
| Trade names | Frisium, others[1] |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a612008 |
| License data | |
| Pregnancy category |
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| Dependence liability | Very high |
| Addiction liability | High |
| Routes of administration | By mouth |
| Drug class | Benzodiazepine |
| ATC code | |
| Legal status | |
| Legal status |
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| Pharmacokinetic data | |
| Bioavailability | 87% (oral) |
| Protein binding | 80–90% |
| Metabolism | Liver |
| Metabolites |
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| Onset of action | 0.5–4 hours |
| Eliminationhalf-life |
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| Excretion | |
| Identifiers | |
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| CAS Number | |
| PubChemCID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.040.810 |
| Chemical and physical data | |
| Formula | C16H13ClN2O2 |
| Molar mass | 300.74 g·mol−1 |
| 3D model (JSmol) | |
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Clobazam, sold under the brand nameFrisium among others, is a long-actingbenzodiazepine derivative used as asedative,anxiolytic, andanticonvulsant[7] that was patented in 1968.[8] Clobazam was first synthesized in 1966 and first published in 1969. It was approved in Australia in 1970 and France in 1974 for short-termanxiety management.[9][10] Marketing for clobazam in the treatment ofepilepsy began in 1984.[11] The primary drug-development goal was to provide greater anxiolytic, anti-obsessive efficacy with fewer benzodiazepine-related side effects.[9] Clobazam is a unique 1,5 benzodiazepine which is used in the United States only as an anticonvulsant. It is available in other countries for the therapy of severe and disabling anxiety in addition to epilepsy. Clobazam has shown a distinct profile and addictive potential compared to the more common benzodiazepines.[12]
In October 2011, the USFood and Drug Administration approved clobazam as an adjunctive treatment forseizures associated withLennox–Gastaut syndrome in adults and children aged two years of age and older. In 2005, clobazam also received approval fromHealth Canada as an add-on therapy for generalized tonic–clonic, myoclonic, and focal impaired awareness seizures.[13]
Clobazam belongs to thebenzodiazepine class of drugs. As a long-acting benzodiazepine derivative it is primarily used as asedative,anxiolytic, and as anadjunctive therapy inepilepsy.
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 withRolandic 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.[15] In addition to epilepsy and severe anxiety, clobazam is approved in the United Kingdom as a short-term (2–4 weeks) adjunctive agent inschizophrenia and otherpsychotic disorders to manageanxiety oragitation.[15][16]
Clobazam is sometimes used for refractory epilepsies. However, long-term prophylactic treatment of epilepsy may have considerable drawbacks, most importantly decreased antiepileptic effects due todrug tolerance which may render long-term therapy less effective.[17] 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 thebenzodiazepine withdrawal syndrome.
Clobazam is approved in Canada for add-on use intonic–clonic,complex partial, andmyoclonic seizures.[18] Clobazam is approved for adjunctive therapy in complex partial seizures,[19] certain types ofstatus epilepticus, specifically themyoclonic,myoclonic-absent,simple partial,complex partial, and tonic varieties,[20] and non-statusabsence 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 chronicanxiety.[21] In Japan, clobazam is approved for adjunctive therapy in treatment-resistantepilepsy featuring complex partial seizures.[22] In New Zealand, clobazam is marketed as Frisium.[23] 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 uncontrolledclinical depression.[15] It was not approved in the United States until October 2011, when it was approved for the adjunctive treatment of seizures associated withLennox–Gastaut syndrome in people aged two years of age or older.[24]
In the United States, clobazam isindicated for use in combination with other medicines to control seizures in people aged two years of age and older who have a specific severe form of epilepsy called Lennox–Gastaut syndrome.[4]
Clinical efficacy and tolerability for management of chronic epilepsy and anxiety disorders has been established in multiple studies.[25]
In September 2020, the USFood and Drug Administration required theboxed 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.[26]
Common side effects include fever, drooling, and constipation.[4]
In December 2013, the USFood and Drug Administration added warnings to the label for clobazam, that it can cause serious skin reactions,Stevens–Johnson syndrome, andtoxic epidermal necrolysis, especially in the first eight weeks of treatment.[27]
Overdose and intoxication with benzodiazepines, including clobazam, may lead toCNS depression, associated with drowsiness, confusion, and lethargy, possibly progressing toataxia,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.[28]
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.[29] Clobazam abuse has been reported in some countries, according to a 1983 World Health Organization report.[30]
In humans, tolerance to the anticonvulsant effects of clobazam may occur[31] and withdrawal seizures may occur during abrupt or over-rapid withdrawal.[32]
Clobazam as with otherbenzodiazepine drugs can lead tophysical dependence,addiction, and what is known as thebenzodiazepine withdrawal syndrome. Withdrawal from clobazam or other benzodiazepines after regular use often leads to withdrawal symptoms which are similar to those seen during alcohol andbarbiturate 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.[33]
Clobazam is predominantly apositive allosteric modulator at theGABAA receptor to increaseGABAergic transmission, particularly chloride conductance in neurons and with some speculated additional activity atsodium channels andvoltage-sensitive calcium channels.[34]
The exact mechanism of action for clobazam, a 1,5-benzodiazepine, which hassedative-hypnotic,anxiolytic, andanticonvulsant effects similar to those produced by other benzodiazepine derivatives, but is apartial agonist at theGABAA receptors. Clobazam is thought to involve the potentiation ofGABAergic neurotransmission resulting from binding at the benzodiazepine site of theGABAA receptor. Like other 1,5-benzodiazepines (for example,arfendazam,lofendazam,triflubazam, andCP-1414S), the active metaboliteN-desmethylclobazam has lessaffinity for theα1 subunit of theGABAA receptor compared to the 1,4-benzodiazepines. It has higher affinity for theα2 subunit of theGABAA receptor, which mediatesanxiolytic effects, than the α1 subunit. Clobazam also has positive modulatory activity.[35][36]
Clobazam and its active metabolite,N-desmethylclobazam (norclobazam), work by enhancingGABA-activatedchloride influx at GABAA receptors,[37] creating ahyperpolarizing,inhibitory postsynaptic potential.[38] It is the primary active metabolite of clobazam, crucial for its prolonged anti-seizure 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 theGABA antagonistflumazenil, and that clobazam acts more efficiently in GABA-deficient brain tissue.[37]
Clobazam has two major metabolites:N-desmethylclobazam and4-hydroxyclobazam, the former of which is active.[39] The demethylation is facilitated byCYP2C19,CYP3A4, andCYP2B6 and the4-hydroxyclobazam byCYP2C18 and CYP2C19.[40]
In children, clobazam half-life values is average 16 hours, while in the elderly, clobazam half-life values are 30 to 48 hours.[41][42]
Clobazam is a 1,5-benzodiazepine, meaning that itsdiazepine ring hasnitrogen atoms at the 1 and 5 positions (instead of the usual 1 and 4).[43]
Clobazam was discovered at the Maestretti Research Laboratories inMilan and was first published in 1969;[44] Maestretti was acquired byRoussel Uclaf[45] which became part ofSanofi.
This article incorporates text from this source, which is in thepublic domain.