What is the recommended dosage and treatment plan for Brivaracetam (Brivaracetam) in patients with epilepsy?

Brivaracetam Dosing and Treatment Plan for Epilepsy

Recommended Dosage

For adults and adolescents ≥16 years with focal (partial-onset) seizures, initiate brivaracetam at 50 mg twice daily (100 mg/day total) without titration, with the option to titrate up to 100 mg twice daily (200 mg/day) based on clinical response and tolerability. 1

Standard Dosing Regimen

• Starting dose: 50 mg twice daily (100 mg/day total) 1, 2
• Therapeutic range: 50-200 mg/day in two divided doses 1, 3
• Maximum dose: 100 mg twice daily (200 mg/day) 1
• No titration required: Brivaracetam can be initiated at the target dose without gradual up-titration 1, 3

Pediatric Dosing (Ages 4-16 years)

Weight-based dosing is necessary for pediatric patients to achieve exposures comparable to adults. 1

• Dosing is calculated based on body weight to achieve plasma concentrations similar to effective adult doses 1
• Oral solution formulation (10 mg/mL) is available for pediatric use 1

Clinical Efficacy Data

Brivaracetam demonstrates significant seizure reduction with 50% responder rates of 32.7-55.8% at 50 mg/day, 36-38.9% at 100 mg/day, and 37.8% at 200 mg/day. 4

• Median seizure reduction rates: 30.5-53.1% for 50 mg/day, 32.5-37.2% for 100 mg/day, and 35.6% for 200 mg/day 4
• Seizure freedom achieved in 3.3% of brivaracetam-treated patients versus 0.5% on placebo (RR 4.74,95% CI 2.00-11.25) 5
• Pooled analysis shows patients on brivaracetam 50-200 mg/day are 1.79 times more likely to achieve ≥50% seizure reduction compared to placebo (95% CI 1.51-2.12) 5

Formulations and Administration Routes

Three interchangeable formulations are available: oral tablets, oral solution (10 mg/mL), and intravenous injection (10 mg/mL). 1

• Tablets: 10 mg, 25 mg, 50 mg, 75 mg, and 100 mg strengths 1
• Oral solution: 10 mg/mL for patients unable to swallow tablets 1
• IV injection: 50 mg/5 mL vial for patients temporarily unable to take oral medication 1
• Food delays absorption (Tmax delayed by 3 hours, Cmax decreased 37%) but does not affect total exposure; can be taken with or without food 1

Special Population Adjustments

Hepatic Impairment

Dose reduction is required for all grades of hepatic cirrhosis due to 50-59% increases in brivaracetam exposure. 1

• Child-Pugh Grade A: 50% increase in exposure 1
• Child-Pugh Grade B: 57% increase in exposure 1
• Child-Pugh Grade C: 59% increase in exposure 1
• Recommended starting dose should be reduced by approximately 50% in all hepatic impairment grades 1

Renal Impairment

Moderate dose adjustment may be considered in severe renal impairment (CrCl <30 mL/min), as brivaracetam AUC increases by 21%. 1

• Less than 10% of brivaracetam is excreted unchanged in urine, so hemodialysis is not expected to enhance clearance 1
• Metabolite accumulation occurs (3-21 fold increases) but metabolites are pharmacologically inactive 1

CYP2C19 Poor Metabolizers

Patients who are CYP2C19 poor metabolizers or taking CYP2C19 inhibitors may require dose reduction, as brivaracetam levels increase by 22-42%. 1

• Genetic variations in CYP2C19 lead to 22% increase (one mutated allele) or 42% increase (both alleles mutated) in brivaracetam blood levels 1

Geriatric Patients

No dose adjustment is necessary for elderly patients, though plasma clearance is slightly reduced (0.76 vs 0.83 mL/min/kg in young adults). 1

Drug Interactions Requiring Dose Modification

Strong Enzyme Inducers

Carbamazepine, phenytoin, and phenobarbital moderately lower brivaracetam plasma concentrations, but no dose adjustment is routinely needed. 6

• Rifampin (more potent CYP inducer) requires consideration of brivaracetam dose adjustment 6
• St. John's wort should be used with caution when starting or stopping during brivaracetam therapy 6

Brivaracetam's Effect on Other Drugs

Brivaracetam inhibits epoxide hydrolase, increasing carbamazepine-epoxide (active metabolite) concentrations, which may require carbamazepine dose reduction if toxicity occurs. 1

• Brivaracetam does not significantly affect levels of other common antiepileptic drugs 1, 6
• No interaction with oral contraceptives 6

Switching from Levetiracetam to Brivaracetam

Immediate switch from levetiracetam to brivaracetam at a 10:1 to 15:1 conversion ratio is feasible without titration, particularly for patients experiencing behavioral side effects with levetiracetam. 4, 5

• This strategy may alleviate behavioral adverse events associated with levetiracetam while maintaining seizure control 4
• Brivaracetam demonstrates better tolerability with less frequent and less severe behavioral adverse events compared to levetiracetam 5

Safety Profile and Monitoring

The most common adverse events are dizziness, somnolence, fatigue, and irritability, with a favorable safety profile similar to placebo across all doses. 4, 2, 5

• Treatment-emergent adverse events occur in approximately 73% during initial treatment period, decreasing to 49% during monotherapy 3
• Behavioral adverse events appear less frequent than with levetiracetam 2, 5
• No significant cardiovascular effects; brivaracetam does not prolong QT interval at doses 4 times the maximum recommended dose 1

Alcohol Interaction Warning

Co-administration with alcohol significantly increases psychomotor impairment, attention deficits, and memory problems beyond either substance alone. 1

• Combined use causes larger decreases in alertness, adaptive tracking, and increases in body sway and reaction time 1
• Patients should be counseled to avoid alcohol consumption during brivaracetam therapy 1

Pharmacokinetic Advantages

Brivaracetam exhibits rapid, nearly complete absorption (bioavailability >95%), linear pharmacokinetics, low protein binding (≤20%), and a 9-hour half-life allowing twice-daily dosing. 1, 6

• Peak plasma concentration (Tmax) occurs at 1 hour (range 0.25-3 hours) 1
• Volume of distribution is 0.5 L/kg, approximating total body water 1
• Minimal drug-drug interactions due to lack of significant effects on CYP enzymes and drug transporters 6

Role in Status Epilepticus

While brivaracetam is not currently included in established status epilepticus guidelines, its intravenous formulation may represent a potential alternative, though clinical experience in this setting is lacking. 4

The 2024 American College of Emergency Physicians guidelines recommend levetiracetam, fosphenytoin, or valproate as second-line agents for benzodiazepine-refractory status epilepticus, with no mention of brivaracetam 7, 8. Given brivaracetam's structural similarity to levetiracetam and favorable pharmacokinetic profile, it may have future utility in acute seizure management, but evidence is currently insufficient 4.