Clobazam, sold under the brand names Frisium, Onfi and others, is a

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

class medication that was patented in 1968. Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxioselective

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

since 1970, and an

anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

since 1984. The primary drug-development goal was to provide greater anxiolytic, anti-obsessive efficacy with fewer benzodiazepine-related side effects.

Medical uses

Clobazam is used for its

effect, and as an adjunctive therapy in

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

. 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. It is not recommended for use in children between the ages of six months and three years, unless there is a compelling need. In addition to epilepsy and severe anxiety, clobazam is approved in the

United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Northwestern Europe, off the coast of European mainland, the continental mainland. It comprises England, Scotlan ...

as a short-term (2–4 weeks) adjunctive agent in

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

and other

psychotic disorders In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or incoh ...

to manage

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

or agitation. 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 Drug tolerance or drug insensitivity is a pharmacological concept describing subjects' reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug's effects; however, this may accelerate tolerance, further ...

which may render long-term therapy less effective. 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 Benzodiazepine withdrawal syndrome (BZD withdrawal) is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines as prescribed develops a physical dependence on them and then reduces the dose or stop ...

. Clobazam is approved in Canada for add-on use in tonic-clonic, complex partial, and myoclonic seizures. Clobazam is approved for adjunctive therapy in complex partial seizures, certain types of

status epilepticus Status epilepticus (SE), or status seizure, is a medical condition with abnormally prolonged seizures. It can have long-term consequences, manifesting as a single seizure lasting more than a defined time (time point 1), or 2 or more seizures over ...

, specifically the myoclonic, myoclonic- absent, simple partial, complex partial, and tonic varieties, and non-status

absence seizure Absence seizures are one of several kinds of generalized seizures. Absence seizures are characterized by a brief loss and return of consciousness, generally not followed by a period of lethargy (i.e. without a notable postictal state). Absence ...

s. 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 chronic

. In Japan, clobazam is approved for adjunctive therapy in treatment-resistant

featuring complex partial seizures. In New Zealand, clobazam is marketed as Frisium 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 Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...

. It was not approved in the United States until 25 October 2011, when it was approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older. The current

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

indicated for use in combination with other medicines is to control seizures in adults and children 2 years and older who have a specific severe form of epilepsy called Lennox-Gastaut syndrome. Clobazam has been FDA-approved for 12 years as of 2023 and it is available in multiple formulations under the brand names Onfi and Sympazan as well as generic formulations.

Contraindications

Clobazam should be used with great care in patients with the following disorders: *

Myasthenia gravis Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, ...

. *

Sleep apnea Sleep apnea (sleep apnoea or sleep apnœa in British English) is a sleep-related breathing disorder in which repetitive Apnea, pauses in breathing, periods of shallow breathing, or collapse of the upper airway during sleep results in poor vent ...

. * Severe

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

diseases such as

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...

and

hepatitis Hepatitis is inflammation of the liver parenchyma, liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), Anorexia (symptom), poor appetite ...

. * Severe

respiratory failure Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a r ...

. Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals, and individuals with

comorbid In medicine, comorbidity refers to the simultaneous presence of two or more medical conditions in a patient; often co-occurring (that is, concomitant or concurrent) with a primary condition. It originates from the Latin term (meaning "sicknes ...

psychiatric disorders A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...

Side effects

In September 2020, the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(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.

Common

Common side effects include fever, drooling, and constipation.

Post-marketing experience

Hives Hives, also known as urticaria, is a kind of skin rash with red or flesh-colored, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and typically ...

. *

Rash A rash is a change of the skin that affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracke ...

es.

Warnings and precautions

In December 2013, the

added warnings to the label for clobazam, that it can cause serious skin reactions,

Stevens–Johnson syndrome Stevens–Johnson syndrome (SJS) is a type of severe skin reaction. Together with toxic epidermal necrolysis (TEN) and #Classification, Stevens–Johnson/toxic epidermal necrolysis (SJS/TEN) overlap, they are considered febrile mucocutaneous d ...

, and

toxic epidermal necrolysis Toxic epidermal necrolysis (TEN), also known as Lyell's syndrome, is a type of severe skin reaction. Together with Stevens–Johnson syndrome (SJS) it forms a spectrum of disease, with TEN being more severe. Early symptoms include fever and f ...

, especially in the first eight weeks of treatment.FDA. 3 December 201
FDA Drug Safety Podcast: FDA warns of serious skin reactions with the anti-seizure drug Onfi (clobazam) and has approved label changes
/ref>

Drug interactions

Alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

increases bioavailability by 50%; compounded depressant effect may precipitate life-threatening toxicity. *

Cimetidine Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers. With the development of proton pump ...

increases the effects of clobazam. *

Valproate Valproate (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with ...

Overdose

Overdose and intoxication with benzodiazepines, including clobazam, may lead to CNS depression, associated with drowsiness, confusion, and lethargy, possibly progressing to

ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...

respiratory depression Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapni ...

, hypotension, and coma or death. The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including alcohol.Fruchtengarten
Inchem - Clobazam
Created July 1997, Reviewed 1998.

Abuse potential and addiction

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. Clobazam abuse has been reported in some countries, according to a 1983 World Health Organization report.

Dependence and withdrawal

In humans, tolerance to the anticonvulsant effects of clobazam may occur and withdrawal seizures may occur during abrupt or over-rapid withdrawal. Clobazam as with other

drugs can lead to

physical dependence Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certa ...

addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...

, and what is known as the

. Withdrawal from clobazam or other benzodiazepines after regular use often leads to withdrawal symptoms which are similar to those seen during alcohol and

barbiturate Barbiturates are a class of depressant, depressant drugs that are chemically derived from barbituric acid. They are effective when used medication, medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological a ...

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.

Pharmacology

Clobazam is predominantly a positive allosteric modulator at the GABA_A receptor with some speculated additional activity at

sodium channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell (biology), cell's cell membrane, membrane. They belong to the Cation channel superfamily, superfamily of cation channels. Classific ...

s and voltage-sensitive calcium channels. Like other 1,5-benzodiazepines (for example, arfendazam, lofendazam, or CP-1414S), the active metabolite ''N''-desmethylclobazam has less

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the α₁ subunit of the GABA_A receptor compared to the 1,4-benzodiazepines. It has higher affinity for α₂ containing receptors, where it has positive modulatory activity. In a double-blind placebo-controlled trial published in 1990 comparing it to

clonazepam Clonazepam, sold under the brand name Klonopin among others, is a benzodiazepine medication used to prevent and treat anxiety disorders, seizures, bipolar mania, agitation associated with psychosis, obsessive–compulsive disorder (OCD), and ...

, 10 mg of clobazam was shown to be less

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...

than either 0.5 mg or 1 mg of clonazepam. The α₁ subtype of the GABA_A receptor, was shown to be responsible for the sedative effects of

diazepam Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...

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. In 1996, Nakamura et al. reported that clobazam and its active metabolite, ''N''-desmethylclobazam (norclobazam), work by enhancing

GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

-activated

chloride The term chloride refers to a compound or molecule that contains either a chlorine anion (), which is a negatively charged chlorine atom, or a non-charged chlorine atom covalently bonded to the rest of the molecule by a single bond (). The pr ...

influx at GABA_A receptors, creating a hyperpolarizing,

inhibitory postsynaptic potential An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential.Purves et al. Neuroscience. 4th ed. Sunderland (MA): Sinauer Associates, Incorporated; 2008. ...

. 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.

Metabolism

Clobazam has two major metabolites: ''N''-desmethylclobazam and 4′-hydroxyclobazam, the former of which is active. The demethylation is facilitated by

CYP2C19 Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some ...

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

, and

CYP2B6 Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances. Func ...

and the ''4''-hydroxyclobazam by CYP2C18 and CYP2C19. In children, clobazam half-life values is average 16 hours, while in the elderly, clobazam half-life values are 30 to 48 hours.

Chemistry

Clobazam is a 1,5-benzodiazepine, meaning that its diazepine ring has

nitrogen Nitrogen is a chemical element; it has Symbol (chemistry), symbol N and atomic number 7. Nitrogen is a Nonmetal (chemistry), nonmetal and the lightest member of pnictogen, group 15 of the periodic table, often called the Pnictogen, pnictogens. ...

atoms at the 1 and 5 positions (instead of the usual 1 and 4). It is not soluble in water and is available in oral form only.

History

Clobazam was discovered at the Maestretti Research Laboratories in Milan and was first published in 1969; Maestretti was acquired by Roussel Uclaf which became part of

Sanofi Sanofi S.A. is a French Multinational corporation, multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 200 ...