Brivaracetam binds to synaptic vesicle protein 2A (SV2A); this is thought to be the primary mechanism for its anticonvulsant activity. SV2A is a transmembrane glycoprotein found presynaptically in neurons and in endocrine cells, and is known to modulate neurotransmitter release.
The related anticonvulsant levetiracetam (Keppra) also binds to SV2A.
Initiated at therapeutic dose
Brivaracetam is available in the form of tablets, an oral solution and a solution for injection or infusion that can be used when oral administration is not feasible temporarily. There is no data on the use of intravenous brivaracetam for longer than 4 days.
Briviact treatment is initiated without titration. Patients should be given a dose of 50mg or 100mg daily in two equal doses. Based on individual patient response and tolerability, the daily dose can be adjusted up to a maximum of 200mg. The dose should be maintained when switching between routes of administration.
Three randomised, double-blind, placebo-controlled trials tested the safety and efficacy of brivaracetam in patients with uncontrolled epilepsy despite already taking one or two anticonvulsants.
The primary endpoint was percent reduction versus placebo in baseline-adjusted partial-onset seizure frequency/week.
Study N01253 - doses 5mg to 50mg
In study N01253 (n=396), patients were given brivaracetam 5mg, 20mg or 50mg daily, or placebo. Most patients (78.3%) were already taking two anticonvulsants.
Patients taking brivaracetam 50mg daily experienced a significant 12.8% reduction in baseline-adjusted partial-onset seizure frequency/week during the 12-week treatment period compared with placebo (p=0.025). A significant reduction was also seen versus placebo in baseline-adjusted partial-onset seizure frequency/28 days in the 50mg group (22.0%, p=0.004).
Study N01252 - doses 20mg to 100mg
Study N01252 (n=398) examined brivaracetam doses of 20mg, 50mg and 100mg daily, and found a significant reduction in baseline-adjusted partial-onset seizure frequency/week versus placebo only in the 100mg group (11.7%, p=0.037).
Study N01358 - doses 100mg to 200mg
A larger study (n=760), N01358, compared brivaracetam 100mg and 200mg with placebo in terms of percent reduction over placebo in 28-day adjusted partial-onset seizure frequency and ≥50% responder rate based on percent reduction in partial-onset seizure frequency from baseline to the treatment period (co-primary endpoints).
Percent reduction over placebo for 28-day adjusted seizure frequency was 22.8% for brivaracetam 100mg (95% CI 13.3-31.2%; p<0.001) and 23.2% for brivaracetam 200mg (95% CI 13.8-31.6%; p<0.001). The ≥50% responder rate was 38.9% for brivaracetam 100mg and 37.8% for brivaracetam 200mg compared with 21.6% for placebo (p<0.001 for both comparisons).
Somnolence and dizziness
The most frequently reported adverse effects of brivaracetam were somnolence (14.3%) and dizziness (11.0%), which were generally mild to moderate in severity. The incidence of somnolence and fatigue increased with increasing dose.
Discontinuation rates due to adverse reactions were 3.5%, 3.4% and 4.0% at daily brivaracetam doses of 50mg, 100mg and 200mg, respectively, compared with 1.7% for placebo. Dizziness and confusion were the adverse reactions most frequently responsible for discontinuation of brivaracetam therapy.
Withdrawal of treatment
Gradual withdrawal of brivaracetam, in weekly increments of 50mg/day, is recommended. Following one week of treatment at 50mg daily, a final week of treatment at 20mg daily is advised.