What is the recommended use of breviracetam in medical treatment?

Breviracetam: Recommended Medical Use

Breviracetam is FDA-approved as adjunctive therapy for partial-onset (focal) seizures in patients 16 years and older, with a standard starting dose of 50 mg twice daily that requires no titration. 1, 2

Primary Indication and Mechanism

• Breviracetam is indicated for the treatment of focal seizures, functioning as a high-affinity ligand for synaptic vesicle protein 2A (SV2A) in the brain, which confers its antiseizure activity 1, 3
• The drug exhibits linear and dose-proportional pharmacokinetics at therapeutic doses, with rapid absorption (median Tmax of 1 hour) and a terminal half-life of approximately 9 hours 1

Dosing and Administration

Standard Dosing

• The FDA-approved dose is 50 mg twice daily (100 mg/day total), with no titration required 1, 2
• The dosing range is 50-200 mg/day, divided into twice-daily administration 1, 2
• Available formulations include oral tablets, oral solution (10 mg/mL), and intravenous solution, which can be used interchangeably 1

Special Population Adjustments

• Hepatic impairment (Child-Pugh A, B, or C): Dose reduction is recommended due to 50-59% increases in brivaracetam exposure 1
• CYP2C19 poor metabolizers: May require dose reduction, as brivaracetam levels increase by 22-42% in individuals with one or both mutated alleles 1
• Severe renal impairment: Brivaracetam AUC increases by 21%, though dose adjustment is not explicitly required by the FDA label 1
• Elderly patients (65-79 years): Plasma clearance is slightly lower (0.76 mL/min/kg vs 0.83 mL/min/kg in young controls), but no specific dose adjustment is mandated 1

Pediatric Dosing

• Weight-based dosing is necessary for pediatric patients 1 month to less than 16 years of age to achieve exposures similar to adults 1
• Estimated plasma clearance varies significantly by weight: 1.09 L/h (11 kg), 1.81 L/h (20 kg), and 3.11 L/h (50 kg) compared to 3.58 L/h in adults (70 kg) 1

Clinical Efficacy

Seizure Control

• In adjunctive therapy trials, brivaracetam demonstrated an 81% increased likelihood of achieving ≥50% seizure reduction compared to placebo (RR 1.81,95% CI 1.53-2.14) 4
• Seizure freedom was achieved 5.89 times more frequently with brivaracetam than placebo (RR 5.89,95% CI 2.30-15.13) 4
• In real-world monotherapy studies, 12-month seizure-freedom rates reached 77.8% overall (75% for first-line monotherapy, 78.4% for conversion-to-monotherapy) 5

Retention Rates

• The 12-month retention rate in monotherapy was 89.9% in clinical practice settings 5
• Treatment withdrawal for any reason was not significantly different from placebo in controlled trials (RR 1.27,95% CI 0.94-1.74) 4

Safety and Tolerability Profile

Common Adverse Events

• The most frequently reported adverse events are somnolence, dizziness, and fatigue 2
• In real-world studies, irritability (12.3%) and dizziness (10.1%) were the most common adverse events 5
• Overall, 39.5% of patients experienced adverse events at 12 months, with most being mild-to-moderate 5

Treatment Discontinuation

• Withdrawal due to adverse events was significantly more likely with brivaracetam than placebo (RR 1.54,95% CI 1.02-2.33) 4
• The most frequent adverse events leading to withdrawal were dizziness (1.8%) and memory problems (1.4%) 5
• The incidence of any adverse events was not significantly different from placebo (RR 1.08,95% CI 1.00-1.17) 4

Drug Interactions

Minimal Interaction Profile

• Brivaracetam has a favorable pharmacokinetic profile with few clinically relevant drug-drug interactions, as it does not interact with most metabolizing enzymes and drug transporters 3
• No dose adjustment is needed when coadministered with most commonly prescribed antiepileptic drugs or oral contraceptives 3
• Brivaracetam is weakly bound to plasma proteins (≤20%), minimizing displacement interactions 1

Enzyme-Inducing Antiepileptic Drugs

• Strong enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital/primidone) moderately lower brivaracetam plasma concentrations, but no adjustment of brivaracetam dose is needed 3
• Rifampin (a potent CYP inducer) requires dose adjustment consideration when coadministered with brivaracetam 3
• Caution is advised when adding or discontinuing St. John's wort, a strong enzyme inducer 3

Specific AED Interactions

• Brivaracetam is a reversible inhibitor of epoxide hydrolase, resulting in increased concentrations of carbamazepine epoxide (an active metabolite of carbamazepine) 1
• Interactions with carbamazepine and phenytoin can be clinically important, though brivaracetam dose adjustment is not required 1

CYP2C19 Inhibitors

• Patients using CYP2C19 inhibitors may require dose reduction, as brivaracetam is metabolized secondarily by CYP2C19 1

Alcohol Interaction Warning

• Coadministration of brivaracetam with alcohol significantly increases the effects of alcohol on psychomotor function, attention, and memory 1
• Combined use causes larger decreases in alertness, adaptive tracking performance, and increases in body sway and reaction time compared to either agent alone 1

Special Populations and Clinical Contexts

Intellectual Disability

• Brivaracetam is a suitable treatment option for patients with intellectual disability and uncontrolled seizures 6
• The 12-month seizure freedom rate was 10.3% in participants with intellectual disability versus 18.4% without, though intellectual disability was not an independent predictor of seizure outcomes 6
• Treatment discontinuation rates (26.4% vs 25.8%) and adverse event profiles were similar regardless of intellectual disability presence or severity 6

Levetiracetam Switchers

• Similar effectiveness and tolerability outcomes were observed in patients switching from levetiracetam to brivaracetam monotherapy 5
• Brivaracetam has greater receptor binding affinity on SV2A than levetiracetam, though clinically significant differences between these agents remain undetermined 2

Elderly Patients

• Brivaracetam demonstrated similar effectiveness and tolerability in elderly patients compared to younger populations 5

Important Clinical Considerations

Not Recommended Uses

• Brivaracetam is NOT recommended for seizure prophylaxis in brain tumor patients, as anticonvulsant prophylaxis is unlikely to be effective in increasing seizure-free survival 7
• For CAR T-cell therapy, levetiracetam (not brivaracetam) is the preferred agent for seizure prophylaxis at 500-750 mg orally every 12 hours for 30 days 7

Limitations of Current Evidence

• Current limitations include lack of head-to-head trials comparing brivaracetam to other antiepileptic drugs, limited long-term safety and efficacy data beyond 12-16 weeks in controlled trials, and higher cost 2
• Only one eligible study included participants with generalized epilepsy, and no studies included participants under age 16 in the systematic review 4
• These findings are primarily applicable to adult patients with drug-resistant focal epilepsy 4

Hemodialysis Considerations

• Less than 10% of brivaracetam is excreted unchanged in urine, so hemodialysis is not expected to enhance clearance 1

Clinical Bottom Line

Brivaracetam represents a viable adjunctive therapeutic option for refractory partial-onset seizures in patients who have failed conventional therapies, offering effective seizure control with minimal drug interactions and no titration requirement. 2, 4 The standard 50 mg twice-daily dose is appropriate for most patients, with adjustments needed only for hepatic impairment, CYP2C19 poor metabolizers, and pediatric weight-based dosing 1