Clobazam

Anxiolytic and Hypnotic Drugs

Drug class: Benzodiazepine, BDZs

Clobazam (FRISIUM)（中文：氯巴占） is a long-acting benzodiazepine with antiepileptic properties. It may be used as an adjunct with other antiepileptics in the treatment of epilepsy including seizzures associated with the Lennox-Gastaut syndrome, although its use may be limited by the development of tolerance or sedation. It is also used in the short-term treatment of acute anxiety.

Drug Names

Generic Name 藥名	HA Code 藥物代碼	Classification藥物分類
Clobazam Tablet 10 mg	CLOB01	P1S1S3 & Part 1 Dangerous Drug

Mechanism of Action

• Clobazam is a benzodiazepine.
• Gama-Aminobutyric acid (GABA) is an inhibitory neurotransmitter, acting on the GABA receptors in the central nervous system (CNS), thus inhibiting the nerve impulses.
• It acts on the benzodiazepine receptors in the brain and the spinal cord. Benzodiazepine receptors in the CNS are linked with GABA receptors as a complex.
• Clobazam by binding to the benzodiazepine receptors results in activation of the GABA-benzodiazepine receptor complex, resulting in inhibition of nerve impulses, overall depression of brain and spinal cord.
• Thus Clobazam use helps to promote muscle relaxation, reduce anxiety, control of convulsions and promote sleep.

Dosage

Epilepsy and myoclonus	By mouth ADULT: Initially 20mg-30mg daily increased if necessary to 60 mg daily Children over 6 years old: Initially 5 mg daily, increase if necessary every 5 days to usualy maintenance dose of 0.3-1mg/kg daily, maximum 60mg
Anxiety	By Mouth Adult: 20-30 daily in divided dose or as a single dose at bedtime, increased up to maximum 60 mg Elderly and debilitated: 10-20 mg daily

Side Effects

Sedative drugs, including alprazolam, have been associated with an increased risk of death.

Possible side effects include:

Very common (>10% of incidence) or Common (1-10% of incidence)	Shakiness and unsteady walk (especially in the elderly) Trembling, and other problems with muscle control or coordination Confusion (especially in the elderly) Amnesia Drowsiness the next day sedation Muscle weakness Paradoxical increase in aggression
Infrequent (0.1 -1% of incidence)	Dysarthria Gastro-intestinal disturbances Gynaecomastia Low blood pressure Incontinence Urinary retention Slurred speech Tremor Vertigo Visual disturbances
Rare (<0.1% of incidence)	Apnoea Blood disorders Jaundice Respiratory depression hypersensitivity reactions suicidal ideation

Overdosage can produce CNS depression and coma.

Paradoxical reactions Although unusual, the following paradoxical reactions have been shown to occur:

• aggression, rage
• mania, agitation, and restlessness
• hallucinations, inappropriate behavior
• twitches and tremor

Pharmacokinetics

Oral bioavailability	Clobazam is well absorbed after oral doses.
Onset of action	Peak plasma concentrations occur within 1 to 4 hours of a dose.
Metabolism	Clobazam is metabolized in the liver
Elimination half-life	Clobazam is eliminated in the urine. Its elimination half-life ranges from about 18-42 hours

Drug Management

Monitoring

• Changes in mood, the development or worsening depression, and/or any thoughts or *ehaviour of suicide.
• Blood pressure and respiratory rate should be monitored
• An increased risk of falls and fractures in elderly, so fall prevention is needed
• Some patients develop blood dyscrasias, and have raised liver enzymes, so periodic blood counts and liver function tests are recommended

Dependence and Withdrawal

• One-third of individuals treated with benzodiazepines for longer than 4 weeks develop a dependence on the drug and experience a withdrawal syndrome upon dose reduction.
• Tolerance develops to the anticonvulsant effects of clonazepam.
• Clonazepam should therefore be withdrawn by tapering the dose to minimize occurrence of withdrawal symptoms.

Drug interaction

Medicines that interact with diazepam may either

• Decrease its effect
• Affect how long it works for
• Increase side effects

Common medications that may interact with diazepam include:

Drugs given with diazepam	Potential Effect
Alcohol, Hypnotics/sedative (e.g. barbiturates) Antidepressants (e.g. fluoxetine, amitriptyline) Sedative histamines (e.g. promethazine) Antipsychotic (e.g. chlorpromazine, clozapine)	May worsens the side effects such as drowsiness , dizziness and respiratory depression
Cimetidine Omeprazole Oxcarbazepine, topiramate, valproate Ketoconazole Itraconazole Isoniazid Erythromycin, ciprofloxacin Propranolol fluoxetine	Prolong the action of clobazam by inhibiting its elimination
Alcohol	May cause a synergistic enhancement of the hypotensive effect of diazepam and alcohol
Oral contraceptives	Oral contraceptives significant decrease the elimination of clobazam, so prolong the action of diazepam
Rifampicin Phenytoin Carbamazepine phenobarbitone	All these drugs increase the metabolism of clobazam, thus decreasing drug levels and effects
Steroid (e.g. Dexamethasone) St John’s wort	Increase the metabolism of clobazam, thus decreasing clobazam plasma levels and effects
Theophylline	May inhibit the action of diazepam
Levodopa (e.g. Sinemet)	clobazam may block the action of levodopa used in the treatment of Parkinson’s disease.
Foods that acidify the urine	Can lead to faster absorption and elimination of clobazam, reducing drug levels and effects.
Food that alkalinize the urine	Can lead to slower absorption and elimination of clobazam, increasing the clobazam plasma levels and effects.

Caution

• particular care in pregnancy,
• elderly, due to increased susceptibility to side-effects, especially loss of coordination and drowsiness
• people with history of alcohol dependence or abuse
• people with history of drug dependence or abuse
• people with psychiatric disorders
• avoid prolonged use and abrupt withdrawal thereafter

Contra-indications

Bromazepam is contraindicated in patients with:

• severe hepatic impairment
• sleep apnoea syndrome
• chronic obstructive airways disease (COPD) with incipient respiratory failure
• Myasthenia gravis
• Acute narrow-angle glaucoma
• Chronic schizophrenia

Hepatic impairment

• Start with smaller initial doses or reduce dose.
• Can precipitate coma.
• Avoid in sever impairment

Renal impairment

• Start with small doses in severe impairment.

Pregnancy

Possible adverse effects of use of benzodiazepines such as Clobazam during pregnancy include: miscarriage, malformation, intrauterine growth retardation, and function deficits.

Breast-feeding

Use during breast feeding is not recommended.

Driving and skilled tasks

May impair judgment and increase reaction time, and so affect ability to drive or operate machinery. Patients should be warned not to operate dangerous machinery or motor vehicles until it is known that they do not become drowsy from clonazepam therapy.

FAQ

How should I take the tablet?

If you get nauseous after taking Clobazam on on an empty stomach, try taking it with food.

What should I avoid while taking?

Do not eat grapefruit or drink grapefruit juice.

Do not drink any alcohol or use recreational drugs while taking clobazam.

What happen if I overdose?

Contact your primary care doctor. If emergency situation, call 999

What happen if I miss a dose?

Take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.