Frisium (Clobazam) in Pediatric Patients
Indications
Frisium (clobazam) is FDA-approved as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. 1
Beyond its FDA-approved indication, clobazam demonstrates broad-spectrum antiepileptic activity and has been used effectively for various intractable childhood epilepsies, including rolandic epilepsy and other refractory seizure disorders. 2, 3, 4
Dosage and Administration in Pediatric Patients
Weight-Based Dosing Strategy
Clobazam dosing is stratified by body weight, with daily doses above 5 mg administered in two divided doses. 1
For Patients ≤30 kg:
- Starting dose: 5 mg daily (can be given as single dose) 1
- Day 7: Increase to 10 mg daily (divided twice daily) 1
- Day 14: Increase to 20 mg daily (divided twice daily) 1
For Patients >30 kg:
- Starting dose: 10 mg daily (divided twice daily) 1
- Day 7: Increase to 20 mg daily (divided twice daily) 1
- Day 14: Increase to 40 mg daily (divided twice daily) 1
Critical Dosing Principles
Do not escalate doses more rapidly than weekly intervals, as clobazam requires 5 days and its active metabolite N-desmethylclobazam requires 9 days to reach steady-state concentrations. 1 This pharmacokinetic reality makes premature dose escalation both ineffective and potentially dangerous.
Each dose within the weight-based range has demonstrated efficacy, though effectiveness increases with higher doses. 1 Individualize the final dose based on seizure control and tolerability, recognizing that some patients achieve optimal control at lower doses within their weight range. 2
Administration Instructions
Clobazam oral suspension can be administered with or without food. 1 The suspension must be shaken well before each dose and measured using only the oral dosing syringe provided with the product. 1 Insert the syringe into the bottle, withdraw the prescribed dose slowly, then administer by slowly squirting into the corner of the patient's mouth. 1
Discontinuation Protocol
To prevent withdrawal reactions, increased seizure frequency, and status epilepticus, taper clobazam by decreasing the total daily dose by 5-10 mg/day on a weekly basis until discontinued. 1 If withdrawal symptoms emerge during tapering, pause the taper or increase back to the previous dose level, then resume tapering more gradually. 1
Pharmacokinetics
Absorption and Distribution
Clobazam acts quickly after oral administration and maintains therapeutic effects for extended durations due to its active metabolite N-desmethylclobazam. 2 Food does not significantly affect absorption, allowing flexible administration timing. 1
Metabolism and Active Metabolite
Clobazam is metabolized primarily via CYP2C19 to its active metabolite N-desmethylclobazam, which contributes significantly to therapeutic activity. 2, 5 This metabolite has a longer half-life than the parent compound, contributing to sustained efficacy. 2
Serum concentrations of clobazam increase with dosage and age, and decrease with concomitant phenobarbital therapy. 5 N-desmethylclobazam levels correlate with clobazam serum levels and age, and are significantly increased by cotherapy with phenytoin or carbamazepine. 5
Patients who are known CYP2C19 poor metabolizers require dosage adjustments, as they will have higher parent drug levels and lower active metabolite levels. 1
Time to Steady State
Clobazam reaches steady-state in approximately 5 days, while N-desmethylclobazam requires approximately 9 days. 1 This pharmacokinetic profile justifies the weekly dose escalation schedule and explains why clinical effects may continue to evolve for over a week after dose changes.
Drug Interactions Affecting Pharmacokinetics
Clobazam significantly reduces the apparent clearance of valproic acid and primidone, potentially leading to elevated levels and toxicity. 5 When adding clobazam to regimens containing valproic acid, monitor closely for adverse effects and consider therapeutic drug monitoring of valproate levels. 5
Conversely, clobazam does not significantly affect the clearance of most other conventional antiepileptics including carbamazepine, phenytoin, or phenobarbital. 5
Strong or moderate CYP2C19 inhibitors may necessitate clobazam dosage adjustments due to altered metabolism. 1
Mechanism of Action
Clobazam allosterically activates GABAA receptors but binds less to subunits mediating sedative effects compared to other benzodiazepines, explaining its favorable tolerability profile. 2 This unique binding profile as a 1,5-benzodiazepine (rather than the more common 1,4-benzodiazepine structure) contributes to its reduced sedation and better tolerability compared to other benzodiazepines. 2, 3
Important Safety Considerations
Clobazam carries boxed warnings for risks from concomitant opioid use, abuse/misuse/addiction potential, and dependence/withdrawal reactions. 1 Concomitant use with opioids may result in profound sedation, respiratory depression, coma, and death; reserve such combinations only when alternative treatments are inadequate. 1
Common adverse effects occurring in ≥10% more frequently than placebo include constipation, somnolence/sedation, pyrexia, lethargy, and drooling. 1 Serious dermatological reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis can occur; discontinue immediately at first sign of rash unless clearly not drug-related. 1
Monitor all patients for suicidal thoughts or behaviors, as with all antiepileptic drugs. 1