Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
Briviact: 50 mg/5 mL (5 mL)
Solution, Oral:
Briviact: 10 mg/mL (300 mL) [contains methylparaben; raspberry flavor]
Tablet, Oral:
Briviact: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg
Pharmacology
Mechanism of Action
The precise mechanism by which brivaracetam exerts its antiepileptic activity is unknown. Brivaracetam displays a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain, which may contribute to the antiepileptic effect.
Pharmacokinetics/Pharmacodynamics
Absorption
Oral: Rapidly and almost completely absorbed; delayed by 3 hours with a high-fat meal.
Distribution
0.5 L/kg
Metabolism
Hepatic and extrahepatic amidase mediated hydrolysis of the amide moiety to form carboxylic acid metabolite (primary route) and hydroxylation primarily by CYP2C19 to form the hydroxy metabolite (secondary route). Metabolites are inactive, including an additional hydroxy acid metabolite.
Excretion
Urine (>95%; <10% unchanged); feces (<1%).
Time to Peak
Oral: 1 hour (fasting, range: 0.25 to 3 hours).
Half-Life Elimination
~9 hours
Protein Binding
≤20% to plasma proteins
Use in Specific Populations
Special Populations: Renal Function Impairment
In adult patients with creatinine clearance <30 mL/minute/1.73 m2 not requiring dialysis, plasma AUC of brivaracetam was moderately increased (21%), while the AUCs of the acid, hydroxy, and hydroxyacid metabolites were increased 3-fold, 4-fold, and 21-fold, respectively. Renal clearance of these inactive metabolites was decreased 10-fold.
Special Populations: Hepatic Function Impairment
In adult patients with hepatic cirrhosis, Child-Pugh classes A, B, and C, showed 50%, 57%, and 59% increases in brivaracetam exposure, respectively; the effect of hepatic impairment is expected to be comparable in pediatric patients.
Special Populations: Elderly
Plasma half-life was 7.9 hours and 9.3 hours in the 65 to 75 and >75 years of age groups, respectively. Steady-state plasma clearance was slightly lower than in younger patients.
Special Populations Note
CYP2C19 poor metabolizers: In patients possessing genetic variations in CYP2C19, production of the hydroxy metabolite is decreased 2-fold or 10-fold, and the blood level of brivaracetam itself is increased by 22% or 42%, respectively, in individuals with one or both mutated alleles.
Use: Labeled Indications
Partial-onset seizures: Treatment of partial-onset seizures in patients with epilepsy as monotherapy or adjunctive therapy.
Contraindications
Hypersensitivity to brivaracetam or any component of the formulation
Dosage and Administration
Dosing: Adult
Partial onset seizures (monotherapy or adjunctive therapy): Oral, IV: Initial: 50 mg twice daily; may decrease to 25 mg twice daily or increase up to 100 mg twice daily based on individual patient response and tolerability (maximum: 200 mg/day). Note: Use injection when oral administration is temporarily not feasible; clinical study experience with brivaracetam injection is limited to 4 consecutive days of treatment.
Dosage adjustment for concomitant therapy with rifampin: Increase brivaracetam dosage by up to 100% (ie, double the brivaracetam dose).
Discontinuation of therapy: Reduce gradually; it has been recommended to reduce the dose by 50 mg/day on a weekly basis with the final week of treatment at the dose of 20 mg/day (Brivlera Canadian product labeling 2016).
Dosing: Geriatric
Refer to adult dosing. Consider starting at the low end of the dosage range.
Dosing: Pediatric
Partial onset seizures: Note: Avoid abrupt withdrawal; decrease dose gradually.
Children ≥4 years and Adolescents <16 years: Oral:
11 to <20 kg: Initial: 0.5 to 1.25 mg/kg/dose twice daily; maximum daily dose: 5 mg/kg/day
20 kg to <50 kg: Initial: 0.5 to 1 mg/kg/dose twice daily; maximum daily dose: 4 mg/kg/day
≥50 kg: Initial: 25 to 50 mg twice daily; maximum daily dose: 200 mg/day
Adolescents ≥16 years: Oral, IV: Initial: 50 mg twice daily; may decrease to 25 mg twice daily or increase up to 100 mg twice daily based on individual patient response and tolerability; maximum daily dose: 200 mg/day. Note: Use injection when oral administration is temporarily not feasible; clinical study experience with brivaracetam injection is limited to 4 consecutive days of treatment.
Dosing adjustment for concomitant therapy with rifampin: Children ≥4 years and Adolescents: Increase brivaracetam dosage by up to 100% (ie, double the brivaracetam dose).
Reconstitution
Injection: May further dilute in D5W, NS, or LR (volume not specified in manufacturer's labeling). Note: May also be administered undiluted.
Administration
IV: Administer IV over 2 to 15 minutes; may administer undiluted or diluted with NS, LR, or D5W.
Oral solution: Administer with or without food. Use a calibrated measuring device to measure (household teaspoon or tablespoon is not an adequate measuring device). May also be administered using a nasogastric tube or gastronomy tube.
Tablets: Administer with or without food. Swallow tablets whole with liquid; do not chew or crush.
Storage
Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).
Oral solution: Do not freeze. Discard any oral solution remaining after 5 months of first opening the bottle.
Injection: Do not freeze. May store solution diluted in NS, LR, or D5W for ≤4 hours at room temperature in polyvinyl chloride (PVC) bags. Discard any unused portion.
Drug Interactions
Alcohol (Ethyl): May enhance the CNS depressant effect of Brivaracetam. Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Consider therapy modification
Cannabidiol: May increase the serum concentration of Brivaracetam. Monitor therapy
Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
CarBAMazepine: Brivaracetam may increase serum concentrations of the active metabolite(s) of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Brivaracetam. Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy
CYP2C19 Inducers (Moderate): May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Monitor therapy
CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
Dabrafenib: May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C19 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy
Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification
Enzalutamide: May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Conversely, concentrations of active metabolites may be increased for those drugs activated by CYP2C19. Management: Concurrent use of enzalutamide with CYP2C19 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C19 substrate should be performed with caution and close monitoring. Consider therapy modification
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification
HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification
LevETIRAcetam: May diminish the therapeutic effect of Brivaracetam. Specifically, the therapeutic effect of brivaracetam may be diminished and/or negligible when given to patients already receiving levetiracetam. Consider therapy modification
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy
Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy
Mianserin: May diminish the therapeutic effect of Anticonvulsants. Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification
Orlistat: May decrease the serum concentration of Anticonvulsants. Monitor therapy
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification
Phenytoin: May decrease the serum concentration of Brivaracetam. Brivaracetam may increase the serum concentration of Phenytoin. Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy
RifAMPin: May decrease the serum concentration of Brivaracetam. Management: Increase the brivaracetam dose by up to 100% (ie, double the dose) if used together with rifampin. Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy
Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification
Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification
Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification
Adverse Reactions
>10%:
Central nervous system: Drowsiness (≤27%), fatigue (≤27%), hypersomnia (≤27%), lethargy (≤27%), malaise (≤27%), sedation (≤27%), abnormal gait (≤16%), ataxia (≤16%), dizziness (≤16%), equilibrium disturbance (≤16%), vertigo (≤16%), psychiatric disturbance (13%; includes psychotic and nonpsychotic)
Neuromuscular & skeletal: Asthenia (≤27%)
Ophthalmic: Nystagmus (≤16%)
1% to 10%:
Central nervous system: Euphoria (IV: ≥3%), infusion site pain (IV: ≥3%), intoxicated feeling (IV: ≥3%), irritability (3%)
Gastrointestinal: Nausea (≤5%), vomiting (≤5%), dysgeusia (IV: ≥3%), constipation (2%)
Hematologic & oncologic: Decreased white blood cell count (2%)
Frequency not defined:
Central nervous system: Suicidal ideation
Hypersensitivity: Hypersensitivity reaction
<1%, postmarketing, and/or case reports: Angioedema, bronchospasm, decreased neutrophils
Warnings/Precautions
Concerns related to adverse effects:
- CNS depression: May cause CNS depression (impaired coordination, ataxia, abnormal gait, dizziness and dose-related fatigue, and somnolence), which may impair physical or mental abilities. Risk is greatest early in treatment, but may occur at any time. Patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
- Hematologic effects: May cause hematologic abnormalities; significant decreased white blood cell count (<3.0 x 109/L) and decreased neutrophil count (<1.0 x 109/L) have been reported.
- Hypersensitivity: Bronchospasm and angioedema have been reported. Discontinue therapy if a hypersensitivity reaction develops. Multiorgan hypersensitivity syndrome (also known as Drug Rash Eosinophilia and Systemic Symptoms or DRESS), is a serious condition sometimes induced by antiepileptic drugs. DRESS initially presents with fever and rash, then with other organ system involvement that may include eosinophilia, lymphadenopathy, hepatitis, nephritis, and/or myocarditis. If any of these hypersensitivity reactions are suspected and an alternative cause cannot be established, discontinue brivaracetam.
- Psychiatric symptoms: Psychosis, paranoia, hallucinations, and behavioral symptoms (including abnormal behavior, adjustment disorder, affect liability, aggression, agitation, altered mood, anger, anxiety, apathy, belligerence, depression, irritability, mood swings, nervousness, psychomotor hyperactivity, restlessness, and tearfulness) may occur; clinical trials reported events in 13% of adult patients receiving brivaracetam compared with 8% receiving placebo (adverse events in pediatric patients were similar to those observed in adult patients).
- Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared with 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify the health care provider immediately if symptoms occur.
Disease-related concerns:
- Hepatic impairment: Use caution in patients with hepatic impairment; dosage adjustment recommended.
- Renal impairment: Not recommended in patients with end-stage renal disease (ESRD) undergoing dialysis.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Special populations:
- CYP2C19 poor metabolizers: Poor metabolizers of CYP2C19 may require dose reduction.
Other warnings/precautions:
- Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.
Monitoring Parameters
CBC with differential, liver and renal function, and symptoms of depression and suicidality (baseline and as clinically indicated)
Pregnancy
Pregnancy Considerations
Adverse events have been observed in animal reproduction studies.
Females exposed to brivaracetam during pregnancy are encouraged to enroll themselves into the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334. Additional information is available at http://www.aedpregnancyregistry.org.
Patient Education
What is this drug used for?
- It is used to treat seizures.
Frequently reported side effects of this drug
- Nausea
- Vomiting
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- Seizures
- Sensing things that seem real but are not
- Mood changes
- Agitation
- Irritability
- Panic attacks
- Behavioral changes
- Change in balance
- Abnormal gait
- Clumsiness
- Involuntary eye movements
- Severe fatigue
- Severe loss of strength and energy
- Severe dizziness
- Depression like thoughts of suicide, anxiety, emotional instability, or confusion.
- Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.
