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Clobazam is a 1,5-benzodiazepine and partial gamma-aminobutyric acid (GABA) receptor agonist, with anxiolytic, sedative, and anticonvulsant activities. Clobazam binds to a specific site, distinct from the inhibitory neurotransmitter GABA binding site, on the benzodiazepine-GABA-A-chloride ionophore receptor complex located in the central nervous system (CNS). This binding causes an allosteric modification of the receptor and enhances the affinity of GABA to the receptor leading to an increase in the opening of chloride-channels. This leads to an increase in chloride ion conductance, neuronal hyperpolarization, inhibition of the action potential and a decrease in neuronal excitability.
Clobazam is a benzodiazepine that is used as an anticonvulsant in the therapy of severe childhood epilepsy. Therapy with clobazam has not been associated with serum aminotransferase elevations, and clinically apparent liver injury from clobazam has yet to be reported and must be rare if it occurs at all.
Mechanism of Action of Clobazam
Clobazam binds at distinct binding sites associated with the chloride ionophore at the post-synaptic GABA receptor. These GABA receptors are in various locations in the CNS (limbic, reticular formation) and clobazam increases the duration of time for which the chloride ionophore is open. As a result, hyperpolarization and stabilization of the membrane occur as the post-synaptic inhibitory effect of GABA is enhanced. Its similar to other benzodiazepines, clobazam binds to the interface of the α and γ2-subunit of the GABA-A receptor. However, it is considered a partial agonist to GABA-A receptors which sets clobazam apart from 1,4-benzodiazepines which are the full agonist. The significance of this difference is that one may experience less sedation with clobazam than with other benzodiazepines. Unlike the endogenous GABA ligand, clobazam binds allosterically to the GABA receptor to increase the frequency of the chloride channel opening and membrane permeability to chloride ions.
Indications of Clobazam
- Anticonvulsants
- Epilepsy
- Lennox-Gastaut Syndrome
- For treatment and management of epilepsy
- seizures associated with Lennox-Gastaut syndrome,
- Treatment form of childhood epilepsy.
- Lennox-gastaut syndrome
- Mixed manic depressive episode
- Panic disorders
- Rapid eye movement sleep disorder
- Restless legs syndrome
- Tardive dyskinesia
- Tremor, essential
- Acute manic episode
- Myoclonic seizures
- Refractory absence Seizures
- For treatment and management of epilepsy and seizures associated with Lennox-Gastaut syndrome, a difficult-to-treat form of childhood epilepsy.
Therapeutic Indications of Clobazam
- Anticonvulsants
- Clobazam is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older.
- Treatment of seizures associated with Lennox-Gastaut syndrome. However, the drug has demonstrated broad anticonvulsant activity and has been used extensively in adults and pediatric patients with a wide range of other seizure disorders, which have sometimes been refractory, including partial, generalized, and myoclonic seizures.
- Clobazam has been used in the treatment of anxiety disorders and has been labeled for the short-term (2-4 weeks) treatment of anxiety in some countries outside the US. However, the drug currently is not FDA-labeled for the treatment of anxiety disorders in the US.
Contraindications of Clobazam
- Myasthenia gravis
- Sleep apnea
- Severe liver diseases such as cirrhosis and hepatitis
- Severe respiratory insufficiency
- In patients with myasthenia gravis (risk of aggravation of muscle weakness).
- In patients with severe respiratory insufficiency (risk of deterioration).
- In patients with sleep apnoea syndrome (risk of deterioration).
- In patients with severe hepatic insufficiencies (risk of precipitating encephalopathy).
- During the first trimester of pregnancy
- In breastfeeding women.
Dosage of Clobazam
Strengths: 5 mg; 10 mg; 20 mg; 2.5 mg/mL
Convulsant or Seizure
- 20mg – 30mg daily divided into 1 or 2 doses, up to 60mg.
- 1 month – 6 years: 250micrograms/kg twice daily, up to 500 micrograms/kg twice daily. From 6 years: 0.3mg/kg – 1mg/kg daily, up to 60mg daily.
Lennox-Gastaut Syndrome
Initial daily dose
- Body weight 30 kg or less: 5 mg orally per day
- Body weight 30 kg or more: 10 mg orally per day
Day 7 total daily dose
- Body weight 30 kg or less: 10 mg orally per day
- Body weight 30 kg or more: 20 mg orally per day
Day 14 daily dose
- Body weight 30 kg or less: 20 mg orally per day
- Body weight 30 kg or more: 40 mg orally per day
Lennox-Gastaut Syndrome
- Initial dose: 5 mg orally per day
Day 7 total daily dose
- Body weight 30 kg or less: 5 mg orally per day
- Body weight 30 kg or more: 10 mg orally per day
Day 14 daily dose
- Body weight 30 kg or less: 10 mg orally per day
- Body weight 30 kg or more: 20 mg orally per day
Maximum dose
- Body weight 30 kg or less: 20 mg/day
- Body weight 30 kg or more: 40 mg/day
Lennox-Gastaut Syndrome
2 years or older, Initial daily dose
- Body weight 30 kg or less: 5 mg orally per day
- Body weight 30 kg or more: 10 mg orally per day
Day 7 total daily dose
- Body weight 30 kg or less: 10 mg orally per day
- Body weight 30 kg or more: 20 mg orally per day
Day 14 daily dose
- Body weight 30 kg or less: 20 mg orally per day
- Body weight 30 kg or more: 40 mg orally per day
Side Effects of Clobazam
The most common
- headache
- Anxiety
- drowsiness
- Dry mouth
- Abdominal or stomach pain
- cold or flu symptoms such as stuffy nose, sore throat, fever;
- Constipation
- hiccups
- coughing
- pain, redness, or hardening of the skin at the injection site
- Nausea ,vomiting,
- painful or swollen gums
- numbness or heavy feeling in the jaw
- stomach pain,
- headache,
- reversible hair loss or thinning, and
- fever
Common
- chills or fever
- headache, severe and throbbing
- joint or back pain
- muscle aching or cramping
- muscle pains or stiffness
- chest pressure or squeezing pain in chest
- excessive sweating
- sudden drowsiness or need to sleep
- coughing up blood
- liver problems–nausea, upper stomach pain, itching, tired feeling, loss of appetite,
Rare
- Anxiety
- change in vision
- chest pain or tightness
- confusion
- cough
- Agitation
- arm, back, or jaw pain
- blurred vision
- chest pain or discomfort
- convulsions
- extra heartbeats
- hallucinations
- headache
- irritability
- lightheadedness
- cold and clammy skin
- fast and shallow breathing
- swelling of your feet, legs, or hands purple spot on your skin caused by internal bleeding
- fast or abnormal heart rate or palpitations
- loss of appetite
- lower back, side, or stomach pain
- mental depression
- muscle pain or cramps
- Swelling of your feet or ankles
- Shortness of breath
- Nausea, fever, dark urine, loss of appetite
- Depression
- Ataxia
- Somnolence (difficulty staying awake)
- Mental confusion
- Hypotension
- Respiratory arrest
- Vasomotor collapse
Drug Interactions of Clobazam
Clobazam may interact with following drugs, supplyments, & may change the efficacy of drugs
- antihistamines (e.g,. cetirizine, diphenhydramine, hydroxyzine, loratadine)
- antipsychotics (e.g., chlorpromazine, clozapine, haloperidol, olanzapine, quetiapine, risperidone)
- aripiprazole
- “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
- baclofen
- barbiturates (e.g., butalbital, phenobarbital)
- benzodiazepines (e.g.diazepam, lorazepam)
- calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
- carbamazepine
- estradiol (birth control pills)
- gabapentin
- macrolide antibiotics (e.g., clarithromycin, erythromycin)
- mirtazapine
- muscle relaxants
- phenytoin
- proton pump inhibitors (e.g., lansoprazole, omeprazole)
- quinolone antibiotics (e.g., ciprofloxacin, ofloxacin)
- selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine, paroxetine, sertraline)
- tapentadol
- theophylline
- tramadol
- tricyclic antidepressasnts (e.g., amitriptyline, clomipramine, desipramine, trimipramine)
Pregnancy & Lactation of Clobazam
FDA Pregnancy Category C
Pregnancy
There are limited amount of data from the use of Clobazam in pregnant women.Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. In animal studies, no congenital malformations have been found in mice, rats and rabbits.
If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuation of the product if she intends to become pregnant or suspects that she is pregnant.
Lactation
Limited information indicates that maternal doses of clobazam up to 30 mg daily produce low levels in milk. Short-term use would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. During long-term administration, monitor the infant for possible sedation and poor sucking.
References
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