Clobazam
Encyclopedia
Clobazam is a drug which is a benzodiazepine
derivative. It has been marketed as an anxiolytic
since 1975 and an anticonvulsant
since 1984. It has also been used incorrectly in combination with several injectable contraceptives.
s certain types of status epilepticus
, specifically the myoclonic, myoclonic-absent
, simple partial
, complex partial
, and tonic varieties, and non-status absence seizures. It is also approved for treatment of anxiety.
In India, clobazam (Frisium, Aventis Pharma
India, Ltd.) is approved for use as an adjunctive therapy in epilepsy and in acute and chronic anxiety
. In Japan, clobazam (Mystan) is approved for adjunctive therapy in treatment-resistant epilepsy
featuring complex partial seizure
s. 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
. It was not approved in the US until October 25, 2011, when it was approved for the treatment of seizures associated with Lennox-Gastaut Syndrome.
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. 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
.
Clobazam is sometimes used for refractory epilepsies. However, long-term prophylactic treatment of epilepsy has considerable drawbacks, most importantly loss of antiepileptic effects due to tolerance which may render long-term therapy ineffective. Other antiepileptic drugs may therefore be preferred for the long term management of epilepsy. Furthermore, benzodiazepines 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
.
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 dose and the longer the drug is taken for, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can however occur from standard dosages and also after short term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.
. 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). Like other 1,5-benzodiazepines (e.g., arfendazam
, lofendazam
, CP-1414S
), it has less affinity for the ω1-allosteric binding site on the GABAA receptor
compared to the 1,4-benzodiazepines. It has selective affinity for the ω2 site, where it has agonist
ic activity.
In a double-blind placebo-controlled trial published in 1990 comparing it to clonazepam
, 10 mg or 20 mg of clobazam was shown to be much less sedating than either 0.5 mg or 1 mg of clonazepam.
The ω1-receptor, which is found on 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. It would seem, then, that the anticonvulsant properties of clobazam are due to its selective affinity for ω2.
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- channel
s. It was also reported that these effects were inhibited by the GABA antagonist
flumazenil
, and that clobazam acts most efficiently in GABA-deficient brain
tissue.
, CYP3A4
, and CYP2B6
and the 4'-hydroxyclobazam by CYP2C18
and CYP2C19.
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
derivative. It has been marketed as an anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
since 1975 and an anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
since 1984. It has also been used incorrectly in combination with several injectable contraceptives.
Indications
As of 2005, clobazam (Frisium) is approved in Canada for adjunctive use in tonic-clonic, complex partial, and myoclonic seizures. Clobazam (Urbanyl) is approved for adjunctive therapy in complex partial seizureSeizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s certain types of status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
, specifically the myoclonic, myoclonic-absent
Absence seizure
Absence seizures are one of several kinds of seizures. These seizures are sometimes referred to as petit mal seizures ....
, simple partial
Simple partial seizure
Simple partial seizures are seizures which affect only a small region of the brain, often the temporal lobes and/or hippocampi. People who have simple partial seizures retain consciousness...
, complex partial
Complex partial seizure
A complex partial seizure is an epileptic seizure that is associated with bilateral cerebral hemisphere involvement and causes impairment of awareness or responsiveness, i.e. loss of consciousness.-Presentation:...
, and tonic varieties, and non-status absence seizures. It is also approved for treatment of anxiety.
In India, clobazam (Frisium, Aventis Pharma
Aventis Pharma
Aventis Pharma Limited , headquartered in Mumbai, is a part of Sanofi-Aventis group. Sanofi-Aventis and its 100% subsidiary Hoechst AG, are the major shareholders of Aventis Pharma Limited...
India, Ltd.) is approved for use as an adjunctive therapy in epilepsy and in acute and chronic anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
. In Japan, clobazam (Mystan) is approved for adjunctive therapy in treatment-resistant epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
featuring complex partial seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s. 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
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
. It was not approved in the US until October 25, 2011, when it was approved for the treatment of seizures associated with Lennox-Gastaut Syndrome.
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. In addition to epilepsy and severe anxiety, clobazam is also approved as a short term (2–4 weeks) adjunctive agent in schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and other psychotic disorders to manage anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
or agitation
Psychomotor agitation
Psychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
.
Clobazam is sometimes used for refractory epilepsies. However, long-term prophylactic treatment of epilepsy has considerable drawbacks, most importantly loss of antiepileptic effects due to tolerance which may render long-term therapy ineffective. Other antiepileptic drugs may therefore be preferred for the long term management of epilepsy. Furthermore, benzodiazepines 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
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
.
Contraindications
Clobazam should be used with great care in patients with the following disorders:- Myasthenia gravisMyasthenia gravisMyasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
- Sleep apneaSleep apneaSleep apnea is a sleep disorder characterized by abnormal pauses in breathing or instances of abnormally low breathing, during sleep. Each pause in breathing, called an apnea, can last from a few seconds to minutes, and may occur 5 to 30 times or more an hour. Similarly, each abnormally low...
- Severe liverLiverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
diseases such as cirrhosisCirrhosisCirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
and hepatitisHepatitisHepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"... - RespiratoryRespiration (physiology)'In physiology, respiration is defined as the transport of oxygen from the outside air to the cells within tissues, and the transport of carbon dioxide in the opposite direction...
problems, including hypoventilationHypoventilationIn medicine, hypoventilation occurs when ventilation is inadequate to perform needed gas exchange...
Special caution
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.Tolerance and dependence
In humans tolerance to the anticonvulsant effects of clobazam frequently occurs and withdrawal seizures can occur during abrupt or overrapid withdrawal.Clobazam as with other benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
drugs can lead to physical dependence
Physical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
, addiction
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...
and what is known as the benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
. Withdrawal from clobazam or other benzodiazepines after regular use often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate
Barbiturate
Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...
withdrawal. The higher the dose and the longer the drug is taken for, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can however occur from standard dosages and also after short term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.
Pharmacology
Clobazam is an anticonvulsantAnticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
. Clobazam is a 1,5-benzodiazepine, meaning that its diazepine
Diazepine
1,2-Diazepine is a seven-membered heterocyclic compound with two nitrogen atoms and three double bonds.-External links:*...
ring has nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
atoms at the 1 and 5 positions (instead of the usual 1 and 4). Like other 1,5-benzodiazepines (e.g., arfendazam
Arfendazam
Arfendazam is a drug which is a benzodiazepine derivative. Arfendazam is a 1,5-benzodiazepine, with the nitrogen atoms located at positions 1 and 5 of the diazepine ring, and so is most closely related to other 1,5-benzodiazepines such as clobazam....
, lofendazam
Lofendazam
Lofendazam is an organic molecule which is a benzodiazepine derivative. Lofendazam is a 1,5-benzodiazepine, with the nitrogen atoms located at positions 1 and 5 of the diazepine ring; therefore, lofendazam is most closely related to other 1,5-benzodiazepines such as clobazam...
, CP-1414S
CP-1414S
CP-1414S is an experimental drug which is a benzodiazepine derivative. CP-1414S is a 1,5-benzodiazepine, with the nitrogen atoms located at positions 1 and 5 of the diazepine ring, and so is most closely related to other 1,5-benzodiazepines such as clobazam....
), it has less affinity for the ω1-allosteric binding site on the GABAA receptor
GABA A receptor
The GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid , the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in...
compared to the 1,4-benzodiazepines. It has selective affinity for the ω2 site, where it has agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
ic activity.
In a double-blind placebo-controlled trial published in 1990 comparing it to clonazepam
Clonazepam
Clonazepamis a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties. It is marketed by Roche under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe...
, 10 mg or 20 mg of clobazam was shown to be much less sedating than either 0.5 mg or 1 mg of clonazepam.
The ω1-receptor, which is found on the α1 subtype of the GABAA receptor, was shown to be responsible for the sedative effects of diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
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. It would seem, then, that the anticonvulsant properties of clobazam are due to its selective affinity for ω2.
In 1996, Nakamura et al. reported that clobazam and its active metabolite, N-desmethylclobazam (norclobazam), work by enhancing GABA
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
-activated chloride
Chloride
The chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...
currents at GABAA-receptor-coupled Cl- channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s. It was also reported that these effects were inhibited by the GABA antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
flumazenil
Flumazenil
Flumazenil is a benzodiazepine antagonist available for injection only, and the only benzodiazepine receptor antagonist on the market today.It was first introduced in 1987 by Hoffmann-La Roche under the trade name Anexate, but only approved by...
, and that clobazam acts most efficiently in GABA-deficient brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
tissue.
Metabolism
Clobazam has two major metabolites: N-desmethyl-clobazam and 4'-hydroxyclobazam, the former of which is active. The demethylation is facilitated by CYP2C19CYP2C19
Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
, CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
, and CYP2B6
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.- Function :...
and the 4'-hydroxyclobazam by CYP2C18
CYP2C18
Cytochrome P450 2C18 is a protein that in humans is encoded by the CYP2C18 gene.-Further reading:...
and CYP2C19.
Drug Interactions
- AlcoholAlcoholIn chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
increases bioavailability by 50% - CimetidineCimetidineCimetidine INN is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers. It is marketed by GlaxoSmithKline under the trade name Tagamet...
increases the effects of clobazam - valproateValproic acidValproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
s
Overdose
Benzodiazepines usually are not fatal when taken alone in overdose but those with underlying health conditions for example respiratory disease or when benzodiazepines are taken in combination with other CNS depressant drugs can result in death.Abuse potential
Clobazam in animal studies has been shown to increase reward seeking behaviours which may suggest an increased risk of addictive behavioural patterns. Significant clobazam abuse has been reported in some countries, according to a 1983 World Health Organisation report.Chemistry
Weber, K. H.; Bauer, A.; Hauptmann, K. H.; Ann. 1972, 756, 128.See also
- BenzodiazepineBenzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
- Benzodiazepine dependenceBenzodiazepine dependenceBenzodiazepine dependence or benzodiazepine addiction is a condition during which a person is dependent on benzodiazepine drugs. Dependence can be either a psychological dependence, physical dependence, or a combination of the two...
- Benzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
- Long term effects of benzodiazepinesLong term effects of benzodiazepinesThe long-term effects of benzodiazepines include drug dependence as well as the possibility of adverse effects on cognitive function, physical health, and mental health. There are significant risks associated with the long-term use of benzodiazepines. However, not all people experience problems...