Usage
Clobazam is an anticonvulsant medication primarily prescribed for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age and older. It is a 1,5-benzodiazepine, classified as a central nervous system (CNS) depressant. Clobazam enhances the effect of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brain. This leads to decreased neuronal excitability and helps prevent seizures.
Alternate Names
Clobazam is the generic name. Brand names include Onfi and Sympazan. Frisium is another name used in some regions.
How It Works
Pharmacodynamics: Clobazam enhances GABAergic inhibition in the CNS by binding to the benzodiazepine site on the GABAA receptor complex. This increases the frequency of chloride channel opening, leading to hyperpolarization of neurons and a decrease in neuronal excitability.
Pharmacokinetics:
- Absorption: Clobazam is well-absorbed orally, with peak plasma concentrations reached in 1 to 4 hours. Food may alter the rate but not the extent of absorption.
- Metabolism: Extensively metabolized in the liver primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. The major active metabolite is N-desmethylclobazam (N-CLB), which contributes significantly to the anticonvulsant effect. N-CLB is further metabolized primarily by CYP2C19.
- Elimination: Clobazam and its metabolites are primarily excreted in the urine. The elimination half-life of clobazam is about 18 hours, while N-CLB has a half-life of approximately 82 hours.
Dosage
Standard Dosage
Adults:
Initial dose: 5 mg orally every 12 hours.
Titrate as tolerated up to a maximum of 40 mg/day divided every 12 hours.
Children (2 years and older):
- ≤ 30 kg: Initial dose: 5 mg orally once daily. Titrate up to a maximum of 20 mg/day. Dose escalations can be made weekly, from 5 mg once daily to 5 mg twice daily, then to 10 mg twice daily.
- > 30 kg: Initial dose: 5 mg orally every 12 hours. Titrate up to a maximum of 40 mg/day divided every 12 hours. Dose escalations can be made weekly, from 5 mg twice daily to 10 mg twice daily, then to 20 mg twice daily.
Special Cases:
- Elderly Patients: Start with 5 mg/day and titrate slowly as tolerated based on weight, generally to half the typical adult dose.
- Patients with Renal Impairment: Dose adjustment is usually not necessary in mild to moderate impairment. For severe impairment, limited data exists and careful monitoring is recommended.
- Patients with Hepatic Dysfunction: Start with 5 mg/day and titrate slowly according to weight, generally to half the typical adult dose. Not recommended in severe hepatic impairment.
- Patients with Comorbid Conditions: Use with caution in patients with respiratory insufficiency, substance abuse history, or psychiatric disorders. Dose adjustments may be needed. Monitor for drug interactions.
- CYP2C19 Poor Metabolizers: Start with 5 mg/day and titrate slowly according to weight, generally to half the typical dose. Dose escalation can be considered after 21 days.
Clinical Use Cases
Clobazam is not indicated for acute management in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations such as status epilepticus or cardiac arrest. Its role is in chronic adjunctive seizure management.
Dosage Adjustments
Adjustments are necessary based on individual patient factors such as renal/hepatic dysfunction, age, weight, comedications, and CYP2C19 metabolizer status as described in special cases above.
Side Effects
Common Side Effects:
Constipation, drowsiness, fatigue, pyrexia (fever), lethargy, drooling, ataxia, and upper respiratory tract infections.
Rare but Serious Side Effects:
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), suicidal thoughts or behaviors, respiratory depression (particularly with concomitant opioid use), withdrawal seizures upon abrupt discontinuation, and physical or psychological dependence.
Long-Term Effects:
Cognitive impairment, behavioral disturbances, and dependence.
Adverse Drug Reactions (ADR):
SJS, TEN, angioedema, anaphylaxis, and severe respiratory depression.
Contraindications
Hypersensitivity to clobazam, myasthenia gravis, severe respiratory insufficiency, acute narrow-angle glaucoma, and sleep apnea syndrome.
Drug Interactions
Clobazam interacts with numerous medications, including:
- CNS Depressants: Alcohol, opioids, barbiturates, and other benzodiazepines can potentiate CNS depression, including respiratory depression.
- CYP3A4 Inducers/Inhibitors: Enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine) can decrease clobazam levels, while inhibitors (e.g., ketoconazole, itraconazole) can increase clobazam levels.
- CYP2C19 Inhibitors: Can increase levels of N-CLB, requiring dosage adjustments.
- Hormonal Contraceptives: Clobazam may decrease the effectiveness of hormonal contraceptives.
Pregnancy and Breastfeeding
Pregnancy Safety Category C. Clobazam can cross the placenta and may cause fetal harm. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clobazam is present in breast milk and may cause adverse effects in infants. Use caution and discuss the risks and benefits with the patient.
Drug Profile Summary
- Mechanism of Action: Enhances GABAergic inhibition by binding to the benzodiazepine site on the GABAA receptor.
- Side Effects: Common: Drowsiness, constipation, fatigue. Serious: SJS/TEN, suicidal thoughts, respiratory depression.
- Contraindications: Hypersensitivity, myasthenia gravis, severe respiratory insufficiency, sleep apnea.
- Drug Interactions: CNS depressants, CYP3A4 and CYP2C19 inducers/inhibitors, hormonal contraceptives.
- Pregnancy & Breastfeeding: Category C; use with caution; present in breast milk.
- Dosage: Adults: Up to 40 mg/day. Children: Up to 20 mg/day (≤30 kg) or 40 mg/day (>30 kg). Adjust for special populations.
- Monitoring Parameters: Seizure frequency, respiratory rate, mental status, liver function tests, and complete blood count.
Popular Combinations
Clobazam is often used in combination with other antiepileptic drugs such as valproate, lamotrigine, levetiracetam, and rufinamide in the management of LGS. These combinations aim for synergistic effects and broader spectrum seizure control.
Precautions
- General Precautions: Assess for allergies, hepatic and renal function, respiratory function, and history of substance abuse.
- Specific Populations: Monitor closely in pregnant women, breastfeeding mothers, children, and the elderly. CYP2C19 poor metabolizers require dosage adjustments.
- Lifestyle Considerations: Avoid alcohol and other CNS depressants. Caution with activities requiring alertness (e.g., driving).
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Clobazam?
A: Adults: Initial 5 mg twice daily, titrated up to 40 mg/day. Children (2 years and older): ≤30 kg: Initial 5 mg once daily, titrated up to 20 mg/day. >30 kg: Initial 5 mg twice daily, titrated up to 40 mg/day. Adjust for special populations.
Q2: How should Clobazam be administered?
A: Orally, with or without food. Tablets can be swallowed whole, chewed, or crushed and mixed with applesauce. The oral suspension should be shaken well before use.
Q3: What are the common side effects of Clobazam?
A: Drowsiness, constipation, fatigue, ataxia, and upper respiratory infections.
Q4: What are the serious side effects of Clobazam?
A: Suicidal thoughts/behavior, SJS/TEN, respiratory depression (especially with opioids), withdrawal seizures upon abrupt discontinuation, and physical/psychological dependence.
Q5: What are the contraindications to Clobazam use?
A: Hypersensitivity to clobazam, myasthenia gravis, severe respiratory insufficiency, acute narrow-angle glaucoma, and sleep apnea syndrome.
Q6: How should Clobazam be discontinued?
A: Gradually taper the dose by 5-10 mg/day weekly to minimize the risk of withdrawal seizures.
Q7: Does Clobazam interact with other medications?
A: Yes, it interacts with CNS depressants, CYP3A4 and CYP2C19 inducers/inhibitors, and hormonal contraceptives.
Q8: Can Clobazam be used during pregnancy?
A: Category C; use only if the potential benefit outweighs the potential risk to the fetus.
Q9: Is Clobazam present in breast milk?
A: Yes, and it can cause adverse effects in nursing infants. Discuss risks/benefits with the patient.
A: Primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. The active metabolite N-CLB is formed and further metabolized by CYP2C19.
