Clobazam, sold under the brand names Frisium and Onfi, among others, is a long-acting benzodiazepine medication primarily used as an anxiolytic and anticonvulsant.[12] Clobazam is a 1,5-benzodiazepine with unique pharmacological characteristics that was patented in 1968.[13][14] Clobazam was first synthesized in 1966 and first published in 1969. It was approved in Australia in 1970 and France in 1974 for short-term anxiety management.[15][16][17] Clobazam is solely approved for use in the United States as a treatment for Lennox–Gastaut syndrome, but the drug is available in other countries as an anti-anxiety agent for the short-term treatment of persistent and debilitating forms of anxiety. It has shown a distinct profile and addictive potential compared to the more common benzodiazepines.[18] 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.

The drug has been approved by Health Canada as an add-on therapy for generalized tonic–clonic, myoclonic, and focal impaired awareness seizures.[19]

In 2011, Lundbeck markets the drug in the United States as Onfi, an adjunctive therapy for seizures associated with Lennox–Gastaut syndrome in patients who are at least two years old.

Medical uses

Frisium (clobazam) 10 mg tablet blister pack

Clobazam (also known as Clobazepam) is a 1,5-benzodiazepine derivative primarily used for adjunctive therapy in severe and disabling forms of anxiety and epilepsy.

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.[20] It is not recommended for use in children between the ages of six months and three years, unless there is a compelling need.[21]

Clobazam is approved in Canada (Frisium) for add-on use in tonic–clonic, complex partial, and myoclonic seizures.[22] Clobazam is approved for adjunctive therapy in complex partial seizures,[23][better source needed] certain types of status epilepticus, specifically the myoclonic, myoclonic-absent, simple partial, complex partial, and tonic varieties,[24][better source needed] and non-status absence seizures.

In the United States, clobazam (Onfi) was not marketed until October 2011 and was only approved for use in combination with other medications to control epilepsy in people aged two years of age and older who have Lennox–Gastaut syndrome.[4][25]

Anxiety

In the United Kingdom, in addition to epilepsy and severe anxiety, clobazam (Frisium) is approved as a short-term (2–4 weeks) adjunctive agent in schizophrenia and other psychotic disorders to manage anxiety or agitation.[21][26] It 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.[21]

Side effects

In September 2020, the US 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.[27]

Common

Common side effects include sedation, drooling, constipation, headaches, trembling hands, digestive problems, low blood pressure, dry mouth, nausea, addiction, physical and psychological dependence.[4]

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.[28]

Dependence and withdrawal

In humans, tolerance to the anticonvulsant effects of clobazam may occur[29][better source needed] and withdrawal seizures may occur during abrupt or over-rapid withdrawal.[30][better source needed]

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.[31][better source needed]

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.[32][better source needed]

Pharmacology

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.[33] 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.[34]

The exact mechanism of action for clobazam, a 1,5-benzodiazepine, which has anxiolytic and anticonvulsant effects similar to those produced by other benzodiazepine derivatives. Clobazam is a potent benzodiazepine receptor 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 anxiolytic and anticonvulsant effects of clobazam.[35][36] 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,[37] creating a hyperpolarizing, inhibitory postsynaptic potential.[5] 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.[11] The primary active metabolite of clobazam, is crucial for its prolonged anti-anxiety and anti-epileptic 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.[37]

Metabolism

Clobazam has four major metabolites: N-desmethylclobazam, 4'-Hydroxy-N-desmethylclobazam, the former of which is active[38] and 4'-Hydroxyclobazam[9] The demethylation is facilitated by CYP2C19, CYP3A4, and CYP2B6 and the 4'-Hydroxyclobazam by CYP2C18 and CYP2C19.[39] 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.[40]

The half-life is approximately 36 to 42 hours for clobazam and 71 to 82 hours for N-desmethylclobazam.[11]

Chemistry

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).[41]

History

Clobazam was discovered at the Maestretti Research Laboratories in Milan in the year 1969.[42] Maestretti was acquired by Roussel Uclaf[43] which became part of Sanofi.

Society and culture

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

Brand names

Name Available forms Available strengths Countries
Onfi Tablets, oral suspension Tablet: 10 mg, 20 mg
Oral suspension: 2.5 mg/mL		 United States
Sympazan Sublingual films 5 mg, 10 mg, 20 mg United States
Frisium Tablets 5 mg, 10 mg, 20 mg Australia, Canada, New Zealand, United Kingdom
Urbanol Capsules, tablets Capsule: 5 mg
Tablet: 10 mg		 South Africa
Urbanyl Tablets 5 mg, 10 mg, 20 mg Belgium, France
Mystan Tablets 5 mg, 10 mg, 20 mg Japan
Clobaday Tablets 5 mg, 10 mg, 20 mg India
Epaclob Oral suspension 5 mg/mL, 10 mg/mL France, Germany, Ireland
Silocalm Oral suspension 5 mg/mL, 10 mg/mL Denmark, Iceland, Spain

See also

References

  1. ↑ "Clobazam". Chemspider.com.
  2. ↑ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  3. ↑ "Frisium 10 mg Tablet Summary of Product Characteristics (SmPC)". electronic medicines compendium (emc). 10 July 2025. Retrieved 22 December 2025.
  4. 1 2 3 "Onfi- clobazam tablet; Onfi- clobazam suspension". DailyMed. 12 March 2024. Retrieved 22 December 2025.
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  6. ↑ "N-desmethylclobazam (CRM) (CAS 22316-55-8)". Caymanchem.com.
  7. ↑ PubChem. "9-Hydroxy-N-desmethylclobazam". PubChem. Retrieved 12 June 2026.
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  37. 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): 728–735. doi:10.1111/j.1528-1157.1996.tb00643.x. PMID 8764810.
  38. ↑ 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): 737–741. doi:10.1097/00007691-200212000-00009. PMID 12451290.
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  41. ↑ 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.
  42. ↑ 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.
  43. ↑ Zirulia G (2014). L'industria delle Medicine. EDRA LSWR. ISBN 978-88-214-3904-9.

Further reading

source: https://en.wikipedia.org/wiki/Clobazam