Clobazam

Registered South African indications:

• Anxiety in neurotic patients
• Pre-operative medication
• Acute symptoms of alcohol withdrawal syndrome

Contraindications

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• History of drug or alcohol dependence (increased risk of development of dependence)
• Myasthenia gravis (risk of aggravation of muscle weakness)
• Severe respiratory insufficiency (risk of deterioration)
• Sleep apnoea syndrome (risk of deterioration)
• Severe impairment hepatic insufficiencies (risk of precipitating encephalopathy)
• During the first trimester of pregnancy
• Breastfeeding
• Clobazam must not be given to children without careful assessment of the need for their use. Clobazam must not be used in children of age 3 years and younger

Contraindications registered in other jurisdictions

• Hypersensitivity to benzodiazepines or any of the excipients in clobazam
• Any history of drug or alcohol dependence (increased risk of development of dependence)
• Myasthenia gravis (risk of aggravation of muscle weakness)
• Severe respiratory insufficiency (risk of deterioration)
• Sleep apnoea syndrome (risk of deterioration)
• Severe hepatic insufficiencies (risk of precipitating encephalopathy)
• During the first trimester of pregnancy
• Breastfeeding
• Benzodiazepines must not be given to children without careful assessment of the need for their use. Clobazam must not be used in children between the ages of 6 months and 3 years, other than in exceptional cases for anticonvulsant treatment where there is a compelling indication

Cautions

• Second and third trimester of pregnancy
• Severe renal impairment 
• Mild to moderate hepatic impairment
• Elderly
• Loss or bereavement 
• Spinal or cerebellar ataxia 
• Personality disorders
• Prolonged use
• High doses
• CYP2C19 poor metabolisers
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery
• Concomitant use with opioids
• Alcohol consumption
• Non-adherence on anti-epileptics (development of tolerance)

Forms avail. in SA and covered in this monograph: cap, tab

South African registered indications and dosages

Anxiety in neurotic patients
Pre-operative medication
Acute symptoms of alcohol withdrawal syndrome

• Oral (cap, tab): 10-30mg, dly; Treatment duration: Generally should not be more than 8-12 weeks, including a tapering off process

Some formulations recommend a secondary dose adjustment whereby after improvement of symptoms, the dose may be reduced

Clobazam is only indicated when disorder is severe, disabling, or subjecting the individual to extreme distress. Clobazam has no specific usefulness in the treatment of psychotic patients

Doses >20mg to be given at bedtime or in divided doses

Treatment should be started with the lowest recommended dose. The maximum dose should not be exceeded

The duration of treatment should be as short as possible. The patient should be reassessed after a period, not exceeding 4 weeks, and regularly thereafter in order to evaluate the need for continued treatment, especially where the patient is free of symptoms. The overall duration of treatment generally should not be more than 8-12 weeks, including a tapering off process. In certain cases, extension beyond the maximum treatment period may be necessary. If so, it should not take place without re-evaluation of the patient's status, using special expertise. It is strongly recommended that prolonged periods of uninterrupted treatment be avoided, since it may lead to dependence

Dosage and duration of treatment must be adjusted to the indication, the severity of the condition, and the individual clinical response

 It is strongly recommended that after prolonged treatment, clobazam is not withdrawn suddenly, but rather that the dose is reduced gradually under medical supervision; otherwise, withdrawal symptoms may occur

The 10mg and 20mg tablets can be divided into equal halves. Clobazam can be given with or without food

The capsules are to be swallowed without chewing with a generous amount of liquid (approximately 1 glass)

Paed. forms avail. in SA and covered in this monograph: cap, tab

South African registered indications and dosages

Anxiety in neurotic patients
Pre-operative medication
Acute symptoms of alcohol withdrawal syndrome

Younger than 3 years

• Contraindicated

Older than 3 years

• No specific recommendation provided, however in children and light-weight patients, the daily dose should be halved

Clobazam is only indicated when disorder is severe, disabling, or subjecting the individual to extreme distress

Benzodiazepines must not be given to children without careful assessment of the need for their use

Increased responsiveness and higher susceptibility to adverse effects may be present in these patients and low initial doses and gradual dose increments, under careful observation, are required

The duration of treatment should be as short as possible. The patient should be reassessed after a period, not exceeding 4 weeks, and regularly thereafter in order to evaluate the need for continued treatment, especially where the patient is free of symptoms. The overall duration of treatment generally should not be more than 8-12 weeks, including a tapering off process. In certain cases, extension beyond the maximum treatment period may be necessary. If so, it should not take place without re-evaluation of the patient's status, using special expertise. It is strongly recommended that prolonged periods of uninterrupted treatment be avoided, since it may lead to dependence

Dosage and duration of treatment must be adjusted to the indication, the severity of the condition, and the individual clinical response

 It is strongly recommended that after prolonged treatment, clobazam is not withdrawn suddenly, but rather that the dose is reduced gradually under medical supervision; otherwise, withdrawal symptoms may occur

The 10mg and 20mg tablets can be divided into equal halves. Clobazam can be given with or without food

The capsules are to be swallowed without chewing with a generous amount of liquid (approximately 1 glass)

Pregnancy

• Caution; second and third trimester
• Contraindicated; first trimester
• There are limited amount of data from the use of Clobazam in pregnant women. Animal studies demonstrated reproductive toxicity including increased incidence of embryo-foetal loss and malformations. In the post-marketing safety database, limited data on exposed pregnancies are available with clobazam. Some of those cases reported foetal or neonatal disorders, but maternal epilepsy and co-administration of anti-epileptic medications were possible confounding factors
• Clobazam is not recommended during pregnancy and in women of childbearing potential not using contraception. Women of childbearing potential should be informed of the risks and benefits of the use of clobazam during pregnancy.If a woman plans a pregnancy or becomes pregnant, carefully evaluate the risks and benefits and whether treatment with clobazam should be discontinued. If clobazam treatment is to be continued, use clobazam at the lowest effective dose
• Administration of clobazam before or during childbirth can result in the occurrence of respiratory depression (including respiratory distress and apnea), which may be associated with other disorders such as sedation signs, hypothermia, hypotonia, and feeding difficulties in the newborn (signs and symptoms of the so-called “floppy infant syndrome”). In the later stages of pregnancy, it must only be used if there are compelling indications. Moreover, infants born to mothers who have taken benzodiazepines over longer periods during the later stages of pregnancy may have developed physical dependence and may be at risk for developing withdrawal symptoms in the postnatal period. Appropriate monitoring of the newborn in the postnatal period is recommended

Breastfeeding

• Contraindicated
• Since benzodiazepines are found in the breast milk, benzodiazepines should not be given to breastfeeding mothers

Fertility 

• No clinical data on fertility available. In a fertility study in male and female rats, no effect on fertility was observed

Renal Impairment

• eGFR ≥30ml/min; No dose adjustment recommended
• eGFR <30ml/min: Caution; dose adjustment recommended
  Initial: 5-10mg dly; Up-titrate gradually; Max: 30mg/24hrs 
  In patients on scheduled-dialysis, give therapy post-dialysis session

Hepatic Impairment

• Mild to moderate: Caution; dose adjustment recommended

• Severe: Contraindicated

Elderly

• Caution; dose adjustment recommended
• Dosage adjustment is the same as for hepatic impairment

Porphyria Information

• Not yet classified (NC)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Sedation
• Fatigue 
• Slowing of reaction time
• Muscle weakness
• Ataxia
• Confusion
• Dizziness
• Numbed emotions
• Headaches
• Fine tremor of the fingers 
• Disorders of articulation
• Unsteadiness of gait and other motor functions
• Loss of libido
• Impaired consciousness
• Anterograde amnesia 
• Amnesia
• Inappropriate behaviour
• Restlessness
• Iritability
• Difficulty falling asleep
• Difficulty sleeping through
• Acute agitational states
• Anxiety
• Aggressiveness
• Nightmares
• Psychosis 
• Suicidal tendencies 
• Muscle spasms 
• Tolerance 
• Physical and/or psychic dependence 
• Withdrawal 
• Rebound phenomena 
• Restlessness

Respiratory Disorders

• Respiratory depression

Gastrointestinal Disorders

• Dryness of the mouth
• Constipation
• Loss of appetite
• Nausea

Endocrine and Metabolic Disorders

• Increased weight

Skin and Subcutaneous Tissue Disorders

• Rash 
• Urticaria
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis

Sensory Disorders

• Visual disorders

• Central nervous system depressants
• Muscle relaxants
• CYP2C19 inhibitors
• CYP2D6 substrates

Respiratory status

Clobazam binds at distinct sites associated with the chloride ionopore at the post-synaptic gamma-aminobutyric acid (GABA) receptos in the limbic system and reticular formation. Clobazam increases the duration of time that the chloride ionopore is open. This shift in chloride ions results in hyperpolarization and stabilization of the membranse, which results in an enhanced post-synaptic inhibitory effect of GABA.

Capsule 5mg

• Urbanol (Sanofi) originator

Tablet 10mg

• Urbanol (Sanofi) originator