Tranquil

• Approved Indications:
• Adjunctive Therapy for Epilepsy: Treatment of seizures in Lennox-Gastaut syndrome, and other types of epilepsy where adjunctive benzodiazepine therapy is appropriate.
• Anxiety Disorders: Short-term management of anxiety and panic disorders.
• Status Epilepticus: Occasionally used as adjunct therapy in prolonged seizures.
• Clinically Accepted Off-Label Uses:
• Management of generalized anxiety disorder (GAD).
• Adjunctive treatment in other refractory epilepsy types.
• Muscle relaxation and sedation in specific neurological conditions.

• Adults:
• Initial dose typically 5–15 mg orally once or twice daily.
• Dose may be titrated gradually based on response and tolerability up to 30 mg daily.
• For epilepsy, starting doses often begin at 5 mg twice daily, adjusted to effect.
• Pediatrics (≥3 years):
• Starting dose is usually 0.25 mg/kg/day, divided into two doses.
• Max dose up to 1 mg/kg/day, not exceeding adult limits.
• Dosage adjustment guided by clinical response and adverse effects.
• Elderly:
• Start with lower doses due to increased sensitivity; typically 5 mg once daily.
• Monitor for sedation and cognitive impairment.
• Special Populations:
• Renal impairment: No specific dose adjustment needed.
• Hepatic impairment: Use caution; dose reduction may be necessary due to reduced metabolism.
• Administration:
• Oral tablets or oral suspension.
• Can be taken with or without food.

Clobazam is a 1,5-benzodiazepine that enhances the effect of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) at the GABA_A receptor complex. It binds to benzodiazepine sites on the receptor, increasing the frequency of chloride channel opening, leading to neuronal hyperpolarization. This action results in anxiolytic, anticonvulsant, muscle relaxant, and sedative effects by depressing abnormal neuronal excitability in the central nervous system.

• Absorption: Rapid and almost complete after oral administration; peak plasma concentrations occur within 0.5 to 4 hours.
• Bioavailability: Approximately 87%.
• Distribution: Widely distributed, crosses the blood-brain barrier; protein binding approximately 80%.
• Metabolism: Extensively metabolized in the liver primarily by CYP3A4 and CYP2C19 enzymes; major active metabolite is N-desmethylclobazam which contributes to pharmacological effects.
• Elimination: Mainly excreted in urine as metabolites.
• Half-life:
• Clobazam: ~36 hours
• N-desmethylclobazam: ~71–82 hours (longer duration of action)

• Pregnancy:
• Classified as FDA Category C.
• Use during pregnancy only if potential benefits justify risks; animal studies show adverse effects but limited human data.
• Risk of neonatal withdrawal or floppy infant syndrome with late pregnancy use.
• Lactation:
• Excreted in breast milk; potential for sedation or respiratory depression in nursing infants.
• Breastfeeding is generally not recommended during treatment.
• Caution: Use only if clearly necessary during pregnancy and lactation.

• Primary Class: Benzodiazepine Antiepileptic and Anxiolytic Agent
• Subclass: 1,5-Benzodiazepine

• Hypersensitivity to clobazam or other benzodiazepines.
• Acute narrow-angle glaucoma.
• Severe respiratory insufficiency.
• Severe hepatic impairment.
• Myasthenia gravis.
• Sleep apnea syndrome.

• Risk of dependence, tolerance, and withdrawal symptoms; gradual dose tapering required to discontinue.
• Use with caution in patients with history of substance abuse.
• May cause respiratory depression, especially with concomitant CNS depressants.
• Potential for sedation, cognitive impairment, and psychomotor slowing; caution in operating machinery.
• Risk of paradoxical reactions including agitation, irritability, and aggression.
• Use cautiously in elderly or debilitated patients.
• Monitor for suicidal ideation and worsening depression.
• Concomitant use with opioids increases risk of profound sedation and respiratory depression.

• Common: Drowsiness, fatigue, dizziness, ataxia, sedation, cognitive impairment.
• Less common: Confusion, behavioral changes, headache, gastrointestinal disturbances (nausea, constipation).
• Serious (rare): Respiratory depression, dependence, withdrawal seizures, hypersensitivity reactions.
• Onset: Sedation usually occurs within hours; tolerance may develop with prolonged use.

• CYP3A4 inhibitors (e.g., ketoconazole, erythromycin) increase clobazam plasma levels, enhancing effects and toxicity risk.
• CYP2C19 inhibitors (e.g., omeprazole) may increase active metabolite levels.
• Other CNS depressants (opioids, alcohol, barbiturates) potentiate sedation and respiratory depression.
• Enzyme inducers (e.g., carbamazepine, phenytoin) may reduce clobazam levels, lowering efficacy.
• Avoid alcohol consumption during treatment.

• Updated epilepsy treatment guidelines emphasize clobazam’s role as adjunctive therapy in Lennox-Gastaut syndrome.
• Warnings about benzodiazepine dependence and withdrawal have been strengthened.
• FDA recommends careful monitoring for respiratory depression when combined with opioids.
• Recent evidence supports cautious use in pediatric populations with tailored dosing.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep container tightly closed.
• Do not freeze.
• Keep out of reach of children.