Combination Therapy: Clobazam and Levetiracetam in Pediatric Epilepsy
Combining clobazam and levetiracetam in children with epilepsy is a rational and well-tolerated strategy that offers synergistic seizure control through complementary mechanisms—GABA enhancement via clobazam and synaptic vesicle protein modulation via levetiracetam—with minimal pharmacokinetic interactions and a manageable side effect profile.
Synergistic Mechanisms and Efficacy
The combination leverages distinct antiepileptic mechanisms that work complementarily rather than redundantly:
Clobazam acts as a 1,5-benzodiazepine that enhances GABAergic inhibition, demonstrating 35.5% complete seizure freedom and 45% achieving >50% seizure reduction when added to existing regimens in children with intractable epilepsy 1
Levetiracetam modulates synaptic vesicle protein SV2A without affecting GABA or glutamate systems directly, showing 68-73% efficacy in refractory status epilepticus and minimal cardiovascular effects 2
The non-overlapping mechanisms allow additive seizure control—clobazam provides broad-spectrum activity across multiple seizure types including Lennox-Gastaut syndrome, while levetiracetam offers consistent efficacy without enzyme induction 1, 2
In pediatric populations specifically, clobazam achieved 41% seizure freedom or >90% reduction when used as add-on therapy, with another 24% showing 50-90% reduction 3
Pharmacokinetic Interactions
The combination exhibits minimal clinically significant drug interactions, which is a major advantage over traditional antiepileptic combinations:
Clobazam does not significantly affect levetiracetam clearance, as levetiracetam is not metabolized through cytochrome P450 pathways and clobazam's interactions are primarily limited to valproic acid and primidone 4, 5
Levetiracetam has minimal drug-drug interactions with other antiepileptics due to its lack of cytochrome P450 enzyme induction or inhibition 5
Monitor for potential elevation of N-desmethylclobazam (clobazam's active metabolite) if enzyme-inducing agents like phenytoin or carbamazepine are also present, though this is not directly caused by levetiracetam 4
Neither agent requires routine therapeutic drug monitoring for the combination itself, though checking levels can verify compliance if seizures remain uncontrolled 4, 2
Side Effect Profile
Clobazam-Specific Adverse Effects
Behavioral disturbances represent the most concerning side effects: severe aggressive outbursts, hyperactivity, insomnia, and depression with suicidal ideation occurred in children requiring medication withdrawal in 35% of cases 3
Sedation, irritability, and ataxia were reported in 22.5% of children, though these often resolved spontaneously or with dose reduction 1
Tolerance development occurred in 38% of children who initially responded to clobazam, with complete tolerance in some cases requiring discontinuation 6
Drooling, balance problems, and mood changes may occur but often improve when 1,4-benzodiazepines are discontinued in favor of clobazam 6
Levetiracetam-Specific Adverse Effects
Behavioral changes including irritability, imbalance, tiredness, and lightheadedness were reported in 11% of patients receiving IV loading doses 7
Minimal cardiovascular effects distinguish levetiracetam from phenytoin and other traditional agents—no significant blood pressure changes, no local infusion site reactions, and no ECG abnormalities in pediatric loading studies 7
Levetiracetam demonstrates superior tolerability compared to oxcarbazepine in some cognitive domains, though oxcarbazepine showed better improvements in choice reaction time and mental rotation in one pediatric study 8
Overlapping and Additive Side Effects
Sedation and somnolence may be additive when combining a benzodiazepine with levetiracetam, requiring careful dose titration and monitoring for excessive CNS depression 7
Behavioral and psychiatric effects from both agents (irritability from levetiracetam, aggression from clobazam) necessitate close monitoring, particularly in children with pre-existing behavioral disorders 3, 7
Respiratory depression risk is primarily attributable to clobazam as a benzodiazepine; have airway equipment available and monitor oxygen saturation, especially during initiation 2
Practical Implementation Algorithm
Initiation Strategy
Start levetiracetam first at 10-20 mg/kg/day divided twice daily, titrating to 30-40 mg/kg/day (maximum 3000 mg/day) over 2-4 weeks to assess baseline efficacy and tolerability 2, 5
Add clobazam only after optimizing levetiracetam to maximum tolerated dose, starting at 0.25-0.5 mg/kg/day and increasing gradually to target 0.8-2 mg/kg/day (maximum 40 mg/day) 1, 3
Monitor for behavioral changes intensively during the first 4-8 weeks after adding clobazam, as this is when aggressive outbursts and mood disturbances typically emerge 3
Verify compliance with serum drug levels before escalating doses or adding additional agents, as non-compliance is a common cause of breakthrough seizures 5
Monitoring Requirements
Seizure frequency documentation at each visit, questioning specifically about seizure occurrences and characteristics 5
Behavioral assessment using standardized scales for attention, mood, aggression, and sleep quality, particularly in the first 3 months 3, 6
Cognitive function evaluation including attention span, alertness, and school performance, as clobazam may improve these parameters compared to 1,4-benzodiazepines 6
EEG monitoring if clinical response is suboptimal or if non-convulsive seizure activity is suspected 5
Critical Pitfalls to Avoid
Do not skip levetiracetam monotherapy optimization before adding clobazam—combination therapy should be reserved for patients who have failed adequate monotherapy at maximum tolerated doses 5
Never use neuromuscular blockers to manage motor manifestations, as they only mask seizures while allowing continued electrical activity and brain injury 2
Avoid abrupt discontinuation of either agent—gradual tapering is essential to prevent withdrawal seizures, particularly with clobazam as a benzodiazepine 5
Do not attribute all behavioral changes to epilepsy—clobazam specifically causes severe psychiatric side effects requiring discontinuation in up to 35% of children 3
Recognize tolerance development to clobazam's antiepileptic effects (38% of responders), which may necessitate dose increases or alternative strategies 6
Search for precipitating factors including sleep deprivation, medication non-compliance, and intercurrent illness before escalating therapy 5