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

Brivaracetam Dosing and Use for Epilepsy

Recommended Dosage

Brivaracetam is FDA-approved for focal (partial-onset) seizures in adults and adolescents ≥16 years at a dose range of 50-200 mg/day, divided into two equal doses, with a recommended starting dose of 50-100 mg/day without titration. 1, 2

Standard Dosing Regimen

• Initial dose: 50-100 mg/day divided into two equal doses (25-50 mg twice daily) 1, 2
• Maintenance dose range: 50-200 mg/day in two divided doses 1, 3
• No titration required: Brivaracetam can be started at the target dose without gradual up-titration 2, 3
• Maximum dose: 200 mg/day (100 mg twice daily) 1, 3

Pediatric Dosing (2 months to <16 years)

• Weight-based dosing is required to achieve exposures similar to adults 1
• Plasma clearance varies significantly by weight: 1.09 L/h at 11 kg, 1.81 L/h at 20 kg, and 3.11 L/h at 50 kg (compared to 3.58 L/h in 70 kg adults) 1

Clinical Efficacy Data

Focal Seizures

• 50 mg/day: Median seizure reduction 30.5-53.1%, with 50% responder rates of 32.7-55.8% 4
• 100 mg/day: Median seizure reduction 32.5-37.2%, with 50% responder rates of 36-38.9% 4
• 200 mg/day: Median seizure reduction 35.6%, with 50% responder rates of 37.8% 4

Secondarily Generalized Tonic-Clonic Seizures (SGTCS)

• 50 mg/day: 66.6% median reduction in SGTCS frequency (p<0.001), with 61.3% achieving ≥50% response 3
• 100 mg/day: 61.2% median reduction (p=0.002), with 55.0% achieving ≥50% response 3
• 200 mg/day: 82.1% median reduction (p<0.001), with 64.0% achieving ≥50% response 3
• Freedom from SGTCS: Achieved in 22.6% (50 mg/day), 31.0% (100 mg/day), and 36.0% (200 mg/day) of patients during 12-week treatment 3

Formulations and Administration Routes

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 vial) 1
• All formulations are interchangeable without dose adjustment 1

Administration Considerations

• Food effects: High-fat meals decrease Cmax by 37% and delay Tmax by 3 hours, but AUC remains unchanged (only 5% decrease), so brivaracetam can be taken with or without food 1
• Median time to peak concentration (Tmax): 1 hour (range 0.25-3 hours) when taken without food 1

Dose Adjustments for Special Populations

Hepatic Impairment

• Child-Pugh A: 50% increase in exposure—consider starting at lower end of dose range 1
• Child-Pugh B: 57% increase in exposure—reduce starting dose 1
• Child-Pugh C: 59% increase in exposure—reduce starting dose 1

Renal Impairment

• Severe renal impairment (CrCl <30 mL/min): 21% increase in brivaracetam AUC, but 3-21 fold increases in inactive metabolites 1
• No dose adjustment typically required as brivaracetam itself is only modestly increased 1
• Hemodialysis: Not expected to enhance clearance as <10% is excreted unchanged in urine 1

Elderly Patients (≥65 years)

• Plasma clearance slightly lower (0.76 mL/min/kg vs 0.83 mL/min/kg in young adults) 1
• Half-life: 7.9 hours (65-75 years) to 9.3 hours (>75 years) 1
• No specific dose adjustment recommended, but monitor for increased sensitivity 1

CYP2C19 Poor Metabolizers

• 22-42% increase in brivaracetam levels depending on genetic variation 1
• Consider dose reduction in CYP2C19 poor metabolizers or when using CYP2C19 inhibitors 1

Drug Interactions Requiring Dose Adjustment

Strong Enzyme Inducers

• Carbamazepine, phenytoin, phenobarbital/primidone: Moderately lower brivaracetam plasma concentrations, but no dose adjustment needed 5
• Rifampin: More potent inducer—dose adjustment should be considered 5
• St. John's wort: Use caution when adding or discontinuing 5

Brivaracetam's Effect on Other Drugs

• Carbamazepine: Brivaracetam inhibits epoxide hydrolase, increasing carbamazepine-epoxide (active metabolite) concentrations—monitor for carbamazepine toxicity 1
• No clinically significant interactions with most other AEDs or oral contraceptives 5

Conversion from Levetiracetam

• Immediate switch is feasible at a conversion ratio of 10:1 to 15:1 (levetiracetam:brivaracetam) 4
• This conversion may alleviate behavioral side effects associated with levetiracetam 4
• Example: Patient on levetiracetam 1000 mg twice daily can switch to brivaracetam 100 mg twice daily (10:1 ratio) 4

Safety and Tolerability Profile

Common Adverse Events

• Most frequent: Fatigue, dizziness, and somnolence 4, 6
• Overall TEAE incidence: 65.0% with brivaracetam ≥50 mg/day vs 60.6% with placebo 3
• Serious TEAEs: 3.9% with brivaracetam vs 3.1% with placebo 3
• Discontinuation due to TEAEs: 6.3% with brivaracetam vs 3.9% with placebo 3

Behavioral Adverse Events

• May be less frequent than with levetiracetam, though this requires further confirmation 6

Alcohol Interaction

• Avoid concurrent alcohol use: Co-administration of brivaracetam 200 mg with alcohol increased psychomotor impairment, decreased alertness, and impaired memory beyond effects of either agent alone 1

Pharmacokinetic Properties

• Absorption: Rapid and nearly complete, with high permeability 1
• Protein binding: Weak (≤20%) 1
• Volume of distribution: 0.5 L/kg (approximates total body water) 1
• Metabolism: Primarily by amidase hydrolysis (hepatic and extra-hepatic), secondarily by CYP2C19 hydroxylation 1
• Elimination: >95% excreted in urine within 72 hours (mostly as metabolites), <10% unchanged 1
• Half-life: Approximately 9 hours 1
• Pharmacokinetics: Linear and dose-proportional at approved doses 1

Critical Clinical Considerations

• No cardiac effects: Does not prolong QT interval at doses up to 4 times the maximum recommended dose 1
• Mechanism of action: High-affinity, selective binding to synaptic vesicle protein 2A (SV2A), with faster brain penetration than levetiracetam 4, 6
• Monotherapy use: FDA-approved for monotherapy in the USA, though limited published data exist 2
• Status epilepticus: IV formulation may be a desirable alternative, but no clinical experience has been reported to date 4