CLOBAZAM

Description

Clobazam is a first-generation AED known under the proprietary brand name of Frisium® (Sanofi, Paris) in the UK and Onfi® (Lundbeck, Copenhagen) in the USA.

Generic formulation

MHRA/ CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (including generic products):

• The need for continued supply of a particular manufacturer’s product should be based on clinical judgment, and consultation with the patient and/ or carer, taking into account factors such as seizure frequency and treatment history.

Indications

Epilepsy: adjunctive therapy of focal and generalized seizures.

Recommendations summarized from NICE (2012)

• Seizure types: adjunctive (generalized tonic- clonic seizures, focal seizures), on referral to tertiary care (absence seizures, myoclonic seizures).
• Epilepsy types: adjunctive (epilepsy with generalized tonic- clonic seizures only), on referral to tertiary care (absence syndromes, juvenile myoclonic epilepsy, idiopathic generalized epilepsy): 
• Psychiatry— short-term relief (2–4 weeks) of severe, disabling, or unacceptably distressing anxiety, occurring alone or in association with insomnia, or shortterm psychosomatic, organic, or psychotic illness (adjunctive treatment in patients with psychotic illness).

Dose titration

• Epilepsy—adjunctive therapy: 20– 30 mg daily (max. 60 mg daily in divided doses).
• Anxiety (short-term use): 20– 30 mg nocte or in divided doses (max. 60 mg daily, in divided doses).

The effectiveness of clobazam may decrease significantly after weeks or months of continuous therapy.

Cautions

• Patients with dependent/ avoidant/ obsessive– compulsive personality disorder (may increase risk of dependence).
• Patients with organic brain damage.
• Patients with muscle weakness.

Interactions

With AEDs
Phenytoin and carbamazepine may cause an increase in the metabolic conversion of clobazam to the active metabolite N- desmethyl clobazam.

With other drugs

• With administration of clobazam (especially at higher doses), an enhancement of the central depressive effect may occur in cases of concomitant use with antipsychotics, hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anticonvulsant drugs, anaesthetics, and sedative antihistamines.
• If clobazam is used concomitantly with narcotic analgesics, possible euphoria may be enhanced (possibly leading to increased psychological dependence).
• The effects of muscle relaxants, analgesics and nitrous oxide may be enhanced by concomitant use of clobazam.
• Dosage adjustment of clobazam may be necessary when co- administered with strong (e.g. fluconazole, fluvoxamine, ticlopidine) or moderate (e.g. omeprazole) CYP2C9 inhibitors, which may result in increased exposure to N- desmethyl clobazam, the active metabolite of clobazam.
• Dose adjustment of drugs metabolized by CYP2D6 (e.g. dextromethorphan, nebivolol, paroxetine, and pimozide) may be necessary, as clobazam is a weak CYP2D6 inhibitor.

With alcohol/food
There is an increased sedative effect when clonazepam or clobazam are given with alcohol, and it is recommended that patients abstain from drinking alcohol during treatment with these drugs.

Special populations

Hepatic impairment

• Start with smaller initial dose or reduce maintenance dose.
• Avoid in severe impairment.

Renal impairment
Start with smaller dose in significant impairment.

Pregnancy

• As a precautionary measure, it is preferable to avoid the use of Clobazam during pregnancy. Clobazam should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
• Administration Clobazam in the last trimester of pregnancy or during labour can result in hypothermia, hypotonia, respiratory depression, and feeding difficulties in the neonate.
• Infants born to mothers who have taken Clobazam during the later stages of pregnancy may develop physical dependence, and may be at risk for developing withdrawal symptoms in the postnatal period.
• Clobazam, like all benzodiazepines, are present in milk and should be avoided if possible during breastfeeding.

Behavioural and cognitive effects in patients with epilepsy

Behavioural effects include sleepiness, poor coordination, and agitation with paradoxical aggression/ disinhibition (usually dose- dependent). Long- term use may result in tolerance, dependence, and withdrawal symptoms if stopped abruptly. In addition to seizure exacerbation, abrupt discontinuation of benzodiazepines can be accompanied by changes in mental status, including anxiety, agitation, confusion, depression, psychosis, and delirium. Benzodiazepines are more frequently associated with adverse cognitive effects than most other AEDs. Among cognitive domains, attention and language appear to be more significantly affected in patients treated with clobazam (mainly at high doses).

Psychiatric use

In addition to its role as an AED, clobazam has an indication for short-term relief (2– 4 weeks) of acute anxiety in patients who have not responded to other drugs, with or without insomnia, and without uncontrolled clinical depression.

Chemical Properties

N/AWhite Solid

Originator

Urbanyl,Diamant,France,1975

Uses

Benzodiazepine psychotherapeutic agent. Clobazam (CLB) has proven efficacy against multiple seizure types. Controlled substance (depressant).

Definition

ChEBI: 7-Chloro-1H-1,5-benzodiazepine-2,4(3H,5H)-dione in which the hydrogen attached to the nitrogen at position 1 is substituted by a methyl group, whilst that attached to the other nitrogen is substitute by a phenyl group. It is used for the short-term management of acute anxiety and as an adjunct in the treatment of epilepsy in association with other antiepileptics.

Manufacturing Process

1.65 g of N-phenyl-N-(2-amino-5-chlorophenyl)-malonic acid ethyl ester amide of MP 108° to 109°C are added to a sodium ethoxide solution, prepared from 20 ml of absolute alcohol and 150 mg of sodium. The solution is allowed to rest for 5 hours at room temperature. Then 1 ml of methyl iodide is added and the reaction mixture is refluxed for 7 hours. After evaporation of the solution in vacuo it is mixed with water and the solution is shaken with
methylene chloride. The methylene chloride phase is dried and evaporated. By treatment of the residue with ethyl acetate/charcoal are isolated 500 mg of 7- chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione of MP 180° to 182°C. The yield amounts to 34% of theory

brand name

Urbanyl (Hoechst- Roussel).

Therapeutic Function

Tranquilizer

Clinical Use

Benzodiazepine:
Anticonvulsant

Anxiolytic

Safety Profile

Poison by ingestion and intraperitoneal routes. Moderately toxic by subcutaneous route. Human systemic effects by ingestion: wakefulness, withdrawal, nausea and vomiting. An experimental teratogen. Other experimental reproductive effects. A tranquhzer. When heated to decomposition it emits very toxic fumes of NOx and Cl-. See also DIAZEPAM.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: metabolism possibly increased by rifampicin.
Antipsychotics: increased sedative effects; serious adverse events reported with clozapine and benzodiazepines.
Antivirals: concentration possibly increased by ritonavir.
Disulfiram: metabolism of clobazam inhibited; increased sedative effects.
Sodium oxybate: enhanced effects of sodium oxybate - avoid.

Metabolism

Clobazam is metabolised in the liver by demethylation and hydroxylation; the cytochrome P450 isoenzyme CYP2C19 plays a role in its metabolism. Unlike the 1,4-benzodiazepines such as diazepam, clobazam, a 1,5-benzodiazepine, is hydroxylated at the 4-position rather than the 3-position.
Clobazam is excreted unchanged and as its main active metabolite, N-desmethylclobazam, mainly in the urine.