Introduction

Anticonvulsant; a pyrrolidine derivative.

Uses for Brivaracetam

Seizure Disorders

Management (in combination with other anticonvulsants) of partial-onset seizures in adults and adolescents ≥16 years of age.

Brivaracetam Dosage and Administration

General

• Avoid abrupt discontinuance; withdraw gradually to minimize potential for increased seizure frequency and status epilepticus. (See Discontinuance of Therapy under Cautions.)

• Closely monitor for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression. (See Suicidality Risk under Cautions.)

Administration

Administer orally (as tablets or solution). May administer IV when oral administration temporarily not feasible; manufacturer states clinical experience with IV use is limited to 4 consecutive days of treatment.

Commercially available brivaracetam tablets, oral solution, and IV injection may be used interchangeably.

Oral Administration

Administer tablets or oral solution twice daily without regard to food.

Do not chew or crush tablets.

Administer oral solution without further dilution.

Use a calibrated measuring device to measure and administer a dose of the oral solution; do not use a household teaspoon or tablespoon.

NG Tube

If necessary, may administer oral solution through a nasogastric or gastric feeding tube.

IV Administration

Administer twice daily as a direct (“bolus”) IV injection or infusion over 2–15 minutes; may administer without further dilution or may be diluted with a compatible solution. (See Compatibility under Stability.)

Contains no preservatives; discard any partially used vials.

Dosage

May initiate therapy with either oral or IV administration.

Gradual dose titration not required when initiating therapy.

Pediatric Patients

Seizure Disorders

Partial Seizures

Adolescents ≥16 years of age: 50 mg twice daily (total daily dose of 100 mg) as tablets or oral solution. May decrease to 25 mg twice daily or increase to 100 mg twice daily based on individual patient response and tolerability.

Adolescents ≥16 years of age: 50 mg twice daily (total daily dose of 100 mg). May decrease to 25 mg twice daily or increase to 100 mg twice daily based on individual patient response and tolerability.

Clinical experience with IV administration is limited to 4 consecutive days of treatment.

Adults

Seizure Disorders

Partial Seizures

50 mg twice daily (total daily dose of 100 mg) as tablets or oral solution. May decrease to 25 mg twice daily or increase to 100 mg twice daily based on individual patient response and tolerability.

50 mg twice daily (total daily dose of 100 mg). May decrease to 25 mg twice daily or increase to 100 mg twice daily based on individual patient response and tolerability.

Clinical experience with IV administration is limited to 4 consecutive days of treatment.

Special Populations

Hepatic Impairment

Patients with any degree of hepatic impairment: Initially, 25 mg twice daily. Do not exceed 75 mg twice daily. (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment necessary. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations. (See Geriatric Use under Cautions.)

Poor CYP2C19 Metabolizers

Dosage reduction may be required. (See Poor CYP2C19 Metabolizers under Cautions.)

Contraindications

• Known hypersensitivity to brivaracetam or any ingredients in the formulation. (See Sensitivity Reactions under Cautions.)

Warnings/Precautions

General Precautions

Suicidality Risk

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%). Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks. Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression. Anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality.

Balance risk of suicidality with risk of untreated illness. Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality. If suicidal thoughts or behavior emerges during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself. (See Advice to Patients.)

Neurologic Effects

Adverse neurologic effects may occur; dizziness, disturbances in gait or coordination (e.g., vertigo, nystagmus, balance disorder, ataxia, abnormal coordination), somnolence, and fatigue reported. Generally observed early in treatment but can occur at any time during therapy.

Monitor patients for adverse neurologic effects and advise patients not to drive or operate machinery until the effects of the drug are known. (See Advice to Patients.)

Psychiatric Effects

Adverse psychiatric effects may occur, including nonpsychotic symptoms (e.g., irritability, anxiety, nervousness, aggression, belligerence, anger, agitation, restlessness, depression, tearfulness, apathy, altered mood, labile affect, psychomotor hyperactivity, abnormal behavior, adjustment disorder) and psychotic symptoms (e.g., psychotic disorder, hallucination, paranoia, acute psychosis).

Monitor patients for adverse psychiatric effects.

Sensitivity Reactions

Hypersensitivity reactions (i.e., bronchospasm, angioedema) reported; discontinue immediately if patients experience a hypersensitivity reaction.

Discontinuance of Therapy

Abrupt withdrawal of anticonvulsants may increase seizure frequency and risk of status epilepticus. In general, gradual withdrawal is recommended; however, manufacturer states that prompt withdrawal may be considered if discontinuance of brivaracetam is necessary because of serious adverse effects.

Abuse Potential and Dependence

Brivaracetam is subject to control as a schedule V (C-V) drug. Sedative and euphoric effects reported less frequently than with alprazolam (a schedule IV drug) at recommended therapeutic doses; however, such effects were similar to those produced by alprazolam when brivaracetam administered at supratherapeutic doses.

No evidence of physical dependence or withdrawal symptoms.

Specific Populations

Pregnancy

Category C.

North American Antiepileptic Drug (NAAED) Pregnancy Registry (for patients) at 888-233-2334 or [Web].

Lactation

Not known whether distributed into human milk; distributes into milk in rats. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in pediatric patients <16 years of age.

Geriatric Use

Insufficient experience in geriatric patients ≥65 years of age to establish efficacy. Consider greater frequency of decreased hepatic, renal, and/or cardiac function and other concomitant disease and drug therapy when selecting dosage in geriatric patients. (See Elimination: Special Populations, under Pharmacokinetics.)

Hepatic Impairment

Systemic exposure of brivaracetam is increased in patients with hepatic impairment. (See Hepatic Impairment under Dosage and Administration, and also see Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

Pharmacokinetics not substantially affected by renal impairment. (See Renal Impairment under Dosage and Administration, and also see Absorption: Special Populations, under Pharmacokinetics.)

Not studied in patients undergoing dialysis; use not recommended.

Poor CYP2C19 Metabolizers

Increased plasma concentrations in patients who are poor metabolizers of CYP2C19. (See Poor CYP2C19 Metabolizers under Dosage and Administration, and also see Absorption: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Somnolence/sedation, dizziness, fatigue, nausea/vomiting, diarrhea, headache, insomnia, nasopharyngitis.

General

• Avoid abrupt discontinuance; withdraw gradually to minimize potential for increased seizure frequency and status epilepticus. (See Discontinuance of Therapy under Cautions.)

• Closely monitor for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression. (See Suicidality Risk under Cautions.)

Administration

Administer orally (as tablets or solution). May administer IV when oral administration temporarily not feasible; manufacturer states clinical experience with IV use is limited to 4 consecutive days of treatment.

Commercially available brivaracetam tablets, oral solution, and IV injection may be used interchangeably.

Oral Administration

Administer tablets or oral solution twice daily without regard to food.

Do not chew or crush tablets.

Administer oral solution without further dilution.

Use a calibrated measuring device to measure and administer a dose of the oral solution; do not use a household teaspoon or tablespoon.

NG Tube

If necessary, may administer oral solution through a nasogastric or gastric feeding tube.

IV Administration

Administer twice daily as a direct (“bolus”) IV injection or infusion over 2–15 minutes; may administer without further dilution or may be diluted with a compatible solution. (See Compatibility under Stability.)

Contains no preservatives; discard any partially used vials.

Dosage

May initiate therapy with either oral or IV administration.

Gradual dose titration not required when initiating therapy.

Pediatric Patients

Seizure Disorders

Partial Seizures

Adolescents ≥16 years of age: 50 mg twice daily (total daily dose of 100 mg) as tablets or oral solution. May decrease to 25 mg twice daily or increase to 100 mg twice daily based on individual patient response and tolerability.

Adolescents ≥16 years of age: 50 mg twice daily (total daily dose of 100 mg). May decrease to 25 mg twice daily or increase to 100 mg twice daily based on individual patient response and tolerability.

Clinical experience with IV administration is limited to 4 consecutive days of treatment.

Adults

Seizure Disorders

Partial Seizures

50 mg twice daily (total daily dose of 100 mg) as tablets or oral solution. May decrease to 25 mg twice daily or increase to 100 mg twice daily based on individual patient response and tolerability.

50 mg twice daily (total daily dose of 100 mg). May decrease to 25 mg twice daily or increase to 100 mg twice daily based on individual patient response and tolerability.

Clinical experience with IV administration is limited to 4 consecutive days of treatment.

Special Populations

Hepatic Impairment

Patients with any degree of hepatic impairment: Initially, 25 mg twice daily. Do not exceed 75 mg twice daily. (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment necessary. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations. (See Geriatric Use under Cautions.)

Poor CYP2C19 Metabolizers

Dosage reduction may be required. (See Poor CYP2C19 Metabolizers under Cautions.)

Metabolized to some extent by CYP2C19 and CYP2C9.

Weak inhibitor of CYP2C19; not expected to be clinically important. Inhibits epoxide hydrolase in vitro. Does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, or 3A4, nor induce CYP1A2, 2B6, 2C9, 2C19, 3A4, or epoxide hydrolase.

Not a substrate of P-glycoprotein (P-gp) or multidrug resistance proteins (MRP) 1 and MRP2. Does not inhibit P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug and toxin extrusion transporters (MATE) 1 and MATE2/K, MRP2, organic anion transporters (OAT) 1 and OAT3, organic cation transporters (OCT) 1 and OCT2, or organic anion transport proteins (OATP) 1B1 and OATP1B3.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP2C19 inhibitors: Potential increased brivaracetam concentrations.

Pharmacokinetic interactions are unlikely with drugs that inhibit other CYP isoenzymes.

CYP2C19 inducers: Potential decreased brivaracetam concentrations.

Specific Drugs