What is the recommended use and dosage of Brivaracetam (Brivaracetam) for treating epilepsy?

Brivaracetam for Epilepsy Treatment

Recommended Use

Brivaracetam is FDA-approved as adjunctive therapy for focal (partial-onset) seizures in adults and adolescents ≥16 years old, and as monotherapy in the USA, with a therapeutic dose range of 50-200 mg/day divided into two equal doses. 1

Mechanism and Clinical Profile

• Brivaracetam acts as a selective, high-affinity ligand for synaptic vesicle protein 2A (SV2A) in the brain, which contributes to its anticonvulsant effect 1, 2
• The drug demonstrates superior SV2A affinity and faster brain penetration compared to levetiracetam 3
• Brivaracetam exhibits linear and time-independent pharmacokinetics at approved doses, with rapid and nearly complete absorption after oral administration 1

Dosing Recommendations

Standard Adult Dosing

The recommended starting dose is 50-100 mg/day (25-50 mg twice daily), with the option to up-titrate to 200 mg/day (100 mg twice daily) based on clinical response. 1, 4

• No titration is required when initiating therapy 4
• Dosing is flexible and can be administered without regard to meals, though high-fat meals delay absorption by 3 hours without affecting total exposure 1

Pediatric Dosing (2 months to <16 years)

• Weight-based dosing is necessary to achieve exposures similar to adults 1
• Plasma clearance varies 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

Special Population Adjustments

Hepatic Impairment:

• Brivaracetam exposure increases by 50% (Child-Pugh A), 57% (Child-Pugh B), and 59% (Child-Pugh C) compared to healthy controls 1
• Dose reduction should be considered in all grades of hepatic cirrhosis 1

Renal Impairment:

• Moderate increase (21%) in plasma AUC with severe renal impairment (CrCl <30 mL/min) 1
• Hemodialysis is not expected to enhance clearance as <10% is excreted unchanged in urine 1

CYP2C19 Poor Metabolizers:

• Blood levels increase by 22% (one mutated allele) or 42% (both mutated alleles) 1
• Dose reduction may be required 1

Geriatric Patients:

• Plasma clearance slightly lower (0.76 mL/min/kg) than young controls (0.83 mL/min/kg) 1
• Consider lower doses due to increased sensitivity in patients >50 years 5

Clinical Efficacy Data

Focal Seizures

• Median seizure reduction rates: 30.5-53.1% (50 mg/day), 32.5-37.2% (100 mg/day), and 35.6% (200 mg/day) 2
• 50% responder rates: 32.7-55.8% (50 mg/day), 36-38.9% (100 mg/day), and 37.8% (200 mg/day) 2

Secondarily Generalized Tonic-Clonic Seizures

Brivaracetam demonstrates particularly strong efficacy for SGTCS, with median reductions of 66.6% (50 mg/day), 61.2% (100 mg/day), and 82.1% (200 mg/day). 6

• ≥50% responder rates: 61.3% (50 mg/day), 55.0% (100 mg/day), and 64.0% (200 mg/day) 6
• Freedom from SGTCS achieved in 22.6% (50 mg/day), 31.0% (100 mg/day), and 36.0% (200 mg/day) of patients 6
• Time to first SGTCS significantly prolonged: 26 days vs 8 days with placebo (hazard ratio 0.55) 6

Drug Interactions

Enzyme-Inducing AEDs

Strong enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital/primidone) moderately lower brivaracetam plasma concentrations, but no dose adjustment is needed. 7

• Rifampin requires dose adjustment consideration due to more potent CYP induction 7
• Caution with St. John's wort when adding or discontinuing treatment 7

Carbamazepine Interaction

• Brivaracetam inhibits epoxide hydrolase, increasing carbamazepine epoxide (active metabolite) concentrations 1
• This interaction can be clinically important and requires monitoring 1

Other Medications

• No clinically relevant interactions with most commonly prescribed AEDs or oral contraceptives 7
• Does not interact with most metabolizing enzymes and drug transporters 7

Safety and Tolerability Profile

Common Adverse Events

• Most frequent: fatigue, dizziness, and somnolence 2, 3
• Treatment-emergent adverse events occur in approximately 65% of patients receiving ≥50 mg/day 6
• Discontinuation due to adverse events: 6.3% (BRV ≥50 mg/day) vs 3.9% (placebo) 6

Behavioral Considerations

Immediate switch from levetiracetam to brivaracetam at a conversion ratio of 10:1 to 15:1 is feasible and may alleviate behavioral side effects associated with levetiracetam. 2

Alcohol Interaction

• Co-administration with alcohol increases effects on psychomotor function, attention, and memory 1
• Larger decreases in alertness and increases in body sway compared to either agent alone 1

Critical Pitfalls to Avoid

• Do not use brivaracetam as first-line monotherapy in newly diagnosed epilepsy—it is primarily indicated for adjunctive therapy in drug-resistant focal seizures 4, 2
• Monitor for increased carbamazepine epoxide levels when co-administering with carbamazepam due to epoxide hydrolase inhibition 1
• Counsel patients about enhanced alcohol effects and advise avoiding alcohol consumption during treatment 1
• Consider dose reduction in hepatic impairment even with mild cirrhosis, as exposure increases by 50% or more 1

Available Formulations

• Tablets: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg 1
• Oral solution: 10 mg/mL 1
• Intravenous injection: 10 mg/mL (50 mg per 5 mL vial) 1
• All formulations are interchangeable 1