Clobazam

Clobazam (marketed under the brand names Frisium, Urbanol, Onfi, and Tapclob) is a benzodiazepine class medication that was patented in 1968.[1] 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 efficacy with fewer benzodiazepine-related side effects.[2]

Clobazam
Clinical data
Trade namesFrisium, Urbanol, Onfi, Tapclob
AHFS/Drugs.comMicromedex Detailed Consumer Information
License data
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration    		Oral (tablets and Oral Suspension)
    ATC code
    Legal status
    Legal status
    • CA: Schedule IV
    • DE: Prescription only (Anlage III for higher doses)
    • NZ: Class C
    • UK: Class C
    • US: Schedule IV
    • In general: ℞ (Prescription only)
    Pharmacokinetic data
    Bioavailability87% (oral)
    Protein binding80–90%
    MetabolismHepatic
    Elimination half-lifeclobazam: 36–42 hours, N-desmethylclobazam: 71–82h
    ExcretionRenal
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.040.810
    Chemical and physical data
    FormulaC16H13ClN2O2
    Molar mass300.74 g·mol−1
    3D model (JSmol)
      (verify)

    Medical uses

    Clobazam is used for epilepsy. It is unclear if there are any benefits to clobazam over other seizure medications for children with Rolandic epilepsy or other epileptic syndromes.[5]

    As of 2005, clobazam is approved in Canada for add-on use in tonic-clonic, complex partial, and myoclonic seizures.[6] Clobazam is approved for adjunctive therapy in complex partial seizures[7] certain types of status epilepticus, specifically the mycolonic, myoclonic-absent, simple partial, complex partial, and tonic varieties,[8] 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.[9] In Japan, clobazam is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures.[10] In New Zealand, clobazam is marketed as Frisium[11] 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.[12] It was not approved in the US 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]

    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.[12] 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.[12]

    Clobazam is also available as an oral suspension in the UK, under the trade name of Tapclob.

    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 tolerance which may render long-term therapy less effective.[14] 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.

    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.[16]

    Side effects

    Common

    Common side effects include fever, lethargy, sleepiness, drooling, and constipation.[17]

    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.[18]

    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.[19]

    Abuse potential and addiction
    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.[20] Clobazam abuse has been reported in some countries, according to a 1983 World Health Organisation report.[21]

    Dependence and withdrawal

    In humans, tolerance to the anticonvulsant effects of clobazam may occur[22] and withdrawal seizures may occur during abrupt or overrapid withdrawal.[23]

    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.[24]

    Pharmacology

    Clobazam is predominantly a positive allosteric modulator at the GABAA receptor with some speculated additionl activity at sodium channels and voltage-sensitive calcium channels.[25]

    Like other 1,5-benzodiazepines (For example, arfendazam, lofendazam, or CP-1414S), the active metabolite N-desmethyl-clobazam 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.[26][27]

    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.[28]

    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.[29]

    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 more efficiently in GABA-deficient brain tissue.[30]

    Metabolism

    Clobazam has two major metabolites: N-desmethyl-clobazam and 4-hydroxyclobazam, the former of which is active.[31] The demethylation is facilitated by CYP2C19, CYP3A4, and CYP2B6 and the 4-hydroxyclobazam by CYP2C18 and CYP2C19.[32]

    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).[33]

    It is not soluble in water and is available in oral form only.[25][19]

    History

    Clobazam was discovered at the Maestretti Research Laboratories in Milan and was first published in 1969;[34] Maestretti was acquired by Roussel Uclaf[35] which became part of Sanofi.

    See also

    References
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    2. Humayun, MJ; Carson, RP (2019). "Clobazam". StatPearls Publishing, Treasure Island (FL). PMID 31082087. Cite journal requires |journal= (help)
    3. Freche, C (1975). "Study of an anxiolytic, clobazam, in otorhinolaryngology in psychosomatic pharyngeal manifestations". Semaine des Hôpitaux. Thérapeutique. 51 (4): 261–3. PMID 5777.
    4. "Clobazam in Treatment of Refractory Epilepsy: The Canadian Experience. A Retrospecti". Epilepsia. 32 (3): 407–16. 1991. doi:10.1111/j.1528-1157.1991.tb04670.x. PMID 2044502.
    5. 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 (10): CD009258. doi:10.1002/14651858.CD009258.pub2. PMID 25280512.
    6. Epilepsy Ontario (2005). "Clobazam". Medications. Archived from the original on 2006-08-18. Retrieved 2006-03-04.
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    8. 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. doi:10.1016/S0370-4475(84)80005-2. PMID 6528075.
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    17. Clobazam label Last updated December 2014
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