Brivaracetam is a 2-pyrrolidine derivative and levetiracetam analog approved for partial onset seizures in patients aged 1 month and older. The efficacy of brivaracetam as adjunctive therapy for partial seizures was evaluated in 3 randomized, double-blind, placebo-controlled, fixed-dose trials including adult patients who were not adequately controlled with 1 or 2 other antiepileptic drugs (n = 1,550). Reductions in 7-day partial onset seizure frequency over placebo were 9.5% to 16.9% for a 50 mg/day regimen and 17% for a 100 mg/day regimen, and 28-day partial onset seizure frequency reductions were 25.2% and 25.7% for 100 mg/day and 200 mg/day regimens, respectively, over placebo. Brivaracetam provided no additional clinical benefit to patients who were receiving concomitant levetiracetam. Similar drug exposure occurs when brivaracetam is used as monotherapy in partial onset seizures. Antiepileptic drugs (AEDs) such as brivaracetam increase the risk of suicidal ideation and behavior; closely monitor all patients receiving brivaracetam for emerging or worsening suicidal thoughts/behavior or depression.
Route-Specific Administration
Oral Administration
-May be administered without regard to meals.
Oral Solid Formulations
Tablets:
-Swallow tablets whole; do not crush or chew.
Oral Liquid Formulations
Oral solution:
-No dilution is necessary.
-Measure and administer the oral solution using a calibrated measuring device.
-A nasogastric tube or gastrostomy tube may be used for administration.
-Storage: Discard any unused solution after 5 months of first opening the bottle.
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if discoloration or particulate matter is present. Brivaracetam injection is a clear, colorless solution.
Intravenous Administration
-Brivaracetam injection may be administered intravenously without further dilution or may be mixed with a diluent, including 0.9% Sodium Chloride Injection, Lactated Ringer's Injection, or 5% Dextrose Injection.
-Infuse over 2 to 15 minutes.
-Storage: After dilution, the solution may be stored for no more than 4 hours at room temperature and may be stored in polyvinyl chloride (PVC) bags. Discard any unused injection vial contents. Brivaracetam injection is for single dose only.
During adjunctive epilepsy clinical trials, neurological adverse reactions were frequently reported with brivaracetam. Among patients who received brivaracetam (n = 803), drowsiness and sedation (16%), dizziness (12%), and fatigue (9%) were observed. A total of 3% of patients had cerebellar coordination and balance disturbances (e.g., ataxia, balance disorder, abnormal coordination, nystagmus, vertigo). Somnolence and fatigue-related reactions (e.g., fatigue, asthenia, malaise, hypersomnia, sedation, lethargy) are dose-dependent, and the risk of occurrence is greatest early in treatment.
During adjunctive epilepsy clinical trials, psychiatric adverse reactions were observed in 13% of patients who received brivaracetam (50 mg/day or more) compared to 8% of patients who received placebo. Irritability with brivaracetam was reported in 3% of patients. Other non-psychotic reactions included anxiety, nervousness, aggression, belligerence, anger, agitation, restlessness, depression, depressed mood, tearfulness, apathy, altered mood, mood swings, emotional lability, psychomotor hyperactivity, abnormal behavior (unspecified), and adjustment disorder. Psychotic reactions observed were psychotic disorder along with hallucinations, paranoia, acute psychosis, and psychotic behavior. Euphoria (3% or more) and feeling drunk (3% or more) have been reported with the use of brivaracetam injection. Psychiatric adverse reactions observed in open-label pediatric trials were generally similar to those observed in adult studies.
Anticonvulsants are thought to carry an increased risk of suicidal ideation and behavior. An analysis by the FDA of previously gathered drug data showed that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor. The increased risk of suicidal ideation and behavior occurred between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks.
During adjunctive epilepsy clinical trials of brivaracetam, patients who received doses of at least 50 mg daily reported nausea or vomiting (5%) and constipation (2%). Dysgeusia was reported in at least 3% of patients with the use of brivaracetam injection. Decreased appetite (anorexia) was observed in pediatric safety studies.
Bronchospasm and angioedema have been reported in patients taking brivaracetam. Brivaracetam is contraindicated in patients with a history of a prior hypersensitivity reaction to brivaracetam or any of the inactive ingredients. If a patient develops a hypersensitivity reaction with brivaracetam therapy, discontinue the drug.
During adjunctive epilepsy clinical trials, 1.8% of brivaracetam-treated patients and 1.1% of placebo-treated patients experienced at least 1 episode of leukopenia (< 3 x 109/L). Neutropenia (< 1 x 109/L) was reported in 0.3% of brivaracetam-treated patients and 0% of placebo-treated patients.
An injection site reaction (infusion site pain) was reported in at least 3% of patients treated with brivaracetam injection during clinical trials.
Brivaracetam is contraindicated for use in patients with a hypersensitivity to brivaracetam or any of the inactive ingredients. Bronchospasm and angioedema have occurred in patients taking brivaracetam.
In January 2008, the FDA alerted healthcare professionals of an increased risk of suicidal ideation and behavior in patients receiving anticonvulsants to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). This alert followed an initial request by the FDA in March 2005 for manufacturers of marketed anticonvulsants to provide data from existing controlled clinical trials for analysis. Prior to this request, preliminary evidence had suggested a possible link between anticonvulsant use and suicidality. The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (5 years of age or more). There were 4 completed suicides among patients in drug treatment groups vs. none in the placebo groups. Patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Data were analyzed from drugs with adequately designed clinical trials including carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. However, this is considered to be a class effect. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. Anticonvulsants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.
Brivaracetam is associated with somnolence, fatigue, dizziness, and coordination or gait disturbances. Patients should be advised to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of whether brivaracetam adversely affects their mental and/or motor performance.
Abrupt discontinuation of brivaracetam therapy should not be undertaken. Brivaracetam and other antiepileptic drugs should be withdrawn gradually to minimize the potential for increased seizure frequency or status epilepticus. Rapid discontinuation may be considered in the case of a serious adverse event.
Adjust the dosage of brivaracetam in patients with hepatic disease. Hepatic impairment increases brivaracetam exposure.
There were insufficient numbers of geriatric patients 65 years of age and older in the double-blind, placebo-controlled epilepsy trials (n = 38) to allow adequate assessment of the effectiveness of brivaracetam in this population. Dose selection for an older adult should be cautious, usually starting at the low end of the dosage range. According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric adults with a history of falls or fractures and should be avoided in these patient populations, except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If brivaracetam must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk.
Data with brivaracetam use in pregnancy are insufficient to identify a risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal studies, brivaracetam was associated with developmental toxicity, including embryofetal mortality, decreased fetal body weights, decreased growth, delayed sexual maturation, and long-term neurobehavioral changes, at doses higher than human therapeutic doses. Encourage pregnant persons who receive brivaracetam to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 1-888-233-2334 or visiting www.aedpregnancyregistry.org.
Brivaracetam is present in human milk. There is insufficient information on the effects of brivaracetam on the breast-fed infant or milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for brivaracetam and any potential adverse effects on the breast-fed infant from brivaracetam or the underlying maternal condition.
Use of brivaracetam is not recommended in patients with end-stage renal disease; there are no data in patients with renal failure undergoing dialysis.
General Dosing Information
-Brivaracetam can be initiated with either IV or oral administration.
-Avoid abrupt withdrawal to minimize the risk of increased seizure frequency and status epilepticus.
For the treatment of partial seizures:
Oral dosage:
Adults: 50 mg PO twice daily. Adjust dosage to 25 to 100 mg PO twice daily based on clinical response and tolerability.
Adolescents 16 to 17 years: 50 mg PO twice daily. Adjust dosage to 25 to 100 mg PO twice daily based on clinical response and tolerability.
Children and Adolescents younger than 16 years weighing 50 kg or more: 25 to 50 mg PO twice daily. Adjust dosage up to 100 mg PO twice daily based on clinical response and tolerability.
Children and Adolescents younger than 16 years weighing 20 to 49 kg: 0.5 to 1 mg/kg/dose PO twice daily. Adjust dosage up to 2 mg/kg/dose PO twice daily based on clinical response and tolerability.
Infants and Children weighing 11 to 19 kg: 0.5 to 1.25 mg/kg/dose PO twice daily. Adjust dosage up to 2.5 mg/kg/dose PO twice daily based on clinical response and tolerability.
Infants and Children weighing less than 11 kg: 0.75 to 1.5 mg/kg/dose PO twice daily. Adjust dosage up to 3 mg/kg/dose PO twice daily based on clinical response and tolerability.
Intravenous dosage:
Adults: 50 mg IV twice daily. Adjust dosage to 25 to 100 mg IV twice daily based on clinical response and tolerability. Use IV route when oral administration is temporarily not feasible. IV therapy beyond 4 consecutive days has not been evaluated in clinical trials.
Adolescents 16 to 17 years: 50 mg IV twice daily. Adjust dosage to 25 to 100 mg IV twice daily based on clinical response and tolerability. Use IV route when oral administration is temporarily not feasible. IV therapy beyond 4 consecutive days has not been evaluated in clinical trials.
Children and Adolescents younger than 16 years weighing 50 kg or more: 25 to 50 mg IV twice daily. Adjust dosage up to 100 mg IV twice daily based on clinical response and tolerability. Use IV route when oral administration is temporarily not feasible. IV therapy beyond 4 consecutive days has not been evaluated in clinical trials.
Children and Adolescents younger than 16 years weighing 20 to 49 kg: 0.5 to 1 mg/kg/dose IV twice daily. Adjust dosage up to 2 mg/kg/dose IV twice daily based on clinical response and tolerability. Use IV route when oral administration is temporarily not feasible. IV therapy beyond 4 consecutive days has not been evaluated in clinical trials.
Infants and Children weighing 11 to 19 kg: 0.5 to 1.25 mg/kg/dose IV twice daily. Adjust dosage up to 2.5 mg/kg/dose IV twice daily based on clinical response and tolerability. Use IV route when oral administration is temporarily not feasible. IV therapy beyond 4 consecutive days has not been evaluated in clinical trials.
Infants and Children weighing less than 11 kg: 0.75 to 1.5 mg/kg/dose IV twice daily. Adjust dosage up to 3 mg/kg/dose IV twice daily based on clinical response and tolerability. Use IV route when oral administration is temporarily not feasible. IV therapy beyond 4 consecutive days has not been evaluated in clinical trials.
Maximum Dosage Limits:
-Adults
200 mg/day PO or IV.
-Geriatric
200 mg/day PO or IV.
-Adolescents
16 to 17 years: 200 mg/day PO or IV.
13 to 15 years weighing 50 kg or more: 200 mg/day PO or IV.
13 to 15 years weighing 20 to 49 kg: 4 mg/kg/day PO or IV.
-Children
weighing 50 kg or more: 200 mg/day PO or IV.
weighing 20 to 49 kg: 4 mg/kg/day PO or IV.
weighing 11 to 19 kg: 5 mg/kg/day PO or IV.
weighing less than 11 kg: 6 mg/kg/day PO or IV.
-Infants
weighing 11 to 19 kg: 5 mg/kg/day PO or IV.
weighing less than 11 kg: 6 mg/kg/day PO or IV.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
The following recommendations are for all stages of hepatic impairment:
-Adults and Adolescents 16 to 17 years: 25 mg PO or IV twice daily initially; Max: 150 mg/day.
-Children and Adolescents weighing 50 kg or more: 25 mg PO or IV twice daily initially; Max: 150 mg/day.
-Children and Adolescents weighing 20 to 49 kg: 0.5 mg/kg/dose PO or IV twice daily initially; Max: 3 mg/kg/day.
-Infants and Children weighing 11 to 19 kg: 0.5 mg/kg/dose PO or IV twice daily initially; Max: 4 mg/kg/day.
-Infants and Children weighing less than 11 kg: 0.75 mg/kg/dose PO or IV twice daily initially; Max: 4.5 mg/kg/day.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Hemodialysis
Use in patients with end-stage renal disease undergoing dialysis is not recommended; there are no data in this population.
*non-FDA-approved indication
Amitriptyline: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Amobarbital: (Minor) Plasma concentrations of brivaracetam may decrease during co-administration with barbiturates. A 19% decrease in the plasma concentration of brivaracetam was observed during co-administration with phenobarbital; however, no dose adjustment is recommended for brivaracetam during concomitant therapy.
Apalutamide: (Major) Increase the dose of brivaracetam by up to 100% in patients taking concomitant apalutamide. Coadministration of brivaracetam with apalutamide may decrease brivaracetam exposure and reduce its efficacy. Brivaracetam is a CYP2C19 substrate and apalutamide is a strong CYP2C19 inducer. Plasma concentrations of brivaracetam were reduced by 45% when administered with another strong CYP2C19 inducer.
Aspirin, ASA; Butalbital; Caffeine: (Minor) Plasma concentrations of brivaracetam may decrease during co-administration with barbiturates. A 19% decrease in the plasma concentration of brivaracetam was observed during co-administration with phenobarbital; however, no dose adjustment is recommended for brivaracetam during concomitant therapy.
Barbiturates: (Minor) Plasma concentrations of brivaracetam may decrease during co-administration with barbiturates. A 19% decrease in the plasma concentration of brivaracetam was observed during co-administration with phenobarbital; however, no dose adjustment is recommended for brivaracetam during concomitant therapy.
Butalbital; Acetaminophen: (Minor) Plasma concentrations of brivaracetam may decrease during co-administration with barbiturates. A 19% decrease in the plasma concentration of brivaracetam was observed during co-administration with phenobarbital; however, no dose adjustment is recommended for brivaracetam during concomitant therapy.
Butalbital; Acetaminophen; Caffeine: (Minor) Plasma concentrations of brivaracetam may decrease during co-administration with barbiturates. A 19% decrease in the plasma concentration of brivaracetam was observed during co-administration with phenobarbital; however, no dose adjustment is recommended for brivaracetam during concomitant therapy.
Butalbital; Acetaminophen; Caffeine; Codeine: (Minor) Plasma concentrations of brivaracetam may decrease during co-administration with barbiturates. A 19% decrease in the plasma concentration of brivaracetam was observed during co-administration with phenobarbital; however, no dose adjustment is recommended for brivaracetam during concomitant therapy.
Butalbital; Aspirin; Caffeine; Codeine: (Minor) Plasma concentrations of brivaracetam may decrease during co-administration with barbiturates. A 19% decrease in the plasma concentration of brivaracetam was observed during co-administration with phenobarbital; however, no dose adjustment is recommended for brivaracetam during concomitant therapy.
Carbamazepine: (Moderate) Coadministration with carbamazepine may increase exposure to the active metabolite of carbamazepine, carbamazepine-epoxide, due to brivaracetam being a reversible inhibitor of epoxide hydrolase. During drug interaction studies, the carbamazepine-epoxide plasma concentration increased up to 198% with a brivaracetam dose of 100 mg twice daily. If tolerability issues arise during concomitant use, carbamazepine dose reduction should be considered. A 26% decrease in the plasma concentration of brivaracetam has also been observed during co-administration with carbamazepine. No dose adjustment is recommended for brivaracetam during concomitant carbamazepine therapy.
Chlordiazepoxide; Amitriptyline: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Clomipramine: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Desipramine: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Doxepin: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants such as brivaracetam. Alcohol consumption may result in additive CNS depression. During a study in healthy subjects, a single brivaracetam dose of 200 mg and an ethanol continuous IV infusion (target blood alcohol concentration of 60 mg/100 mL during 5 hours) increased the effects of alcohol on psychomotor function, alertness, attention span, body sway, saccadic reaction time, and memory.
Fosphenytoin: (Major) Phenytoin plasma concentrations may increase up to 20% during concomitant treatment with brivaracetam. Monitoring of phenytoin concentrations is recommended when brivaracetam is added to or discontinued from ongoing fosphenytoin treatment. A 21% decrease in the plasma concentration of brivaracetam has also been observed during co-administration with phenytoin. No dose adjustment is recommended for brivaracetam during concomitant fosphenytoin therapy.
Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as brivaracetam. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
Imipramine: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Co-administration of brivaracetam with rifampin decreases brivaracetam plasma concentrations by 45%, likely because of CYP2C19 induction. When metabolized, brivaracetam undergoes hydroxylation that is mediated by CYP2C19. The dose of brivaracetam should be increased by up to 100% in patients in patients taking concomitant rifampin.
Isoniazid, INH; Rifampin: (Major) Co-administration of brivaracetam with rifampin decreases brivaracetam plasma concentrations by 45%, likely because of CYP2C19 induction. When metabolized, brivaracetam undergoes hydroxylation that is mediated by CYP2C19. The dose of brivaracetam should be increased by up to 100% in patients in patients taking concomitant rifampin.
Methohexital: (Minor) Plasma concentrations of brivaracetam may decrease during co-administration with barbiturates. A 19% decrease in the plasma concentration of brivaracetam was observed during co-administration with phenobarbital; however, no dose adjustment is recommended for brivaracetam during concomitant therapy.
Nortriptyline: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Pentobarbital: (Minor) Plasma concentrations of brivaracetam may decrease during co-administration with barbiturates. A 19% decrease in the plasma concentration of brivaracetam was observed during co-administration with phenobarbital; however, no dose adjustment is recommended for brivaracetam during concomitant therapy.
Perphenazine; Amitriptyline: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Phenobarbital: (Minor) Plasma concentrations of brivaracetam may decrease during co-administration with barbiturates. A 19% decrease in the plasma concentration of brivaracetam was observed during co-administration with phenobarbital; however, no dose adjustment is recommended for brivaracetam during concomitant therapy.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Minor) Plasma concentrations of brivaracetam may decrease during co-administration with barbiturates. A 19% decrease in the plasma concentration of brivaracetam was observed during co-administration with phenobarbital; however, no dose adjustment is recommended for brivaracetam during concomitant therapy.
Phenytoin: (Major) Phenytoin plasma concentrations may increase up to 20% during concomitant treatment with brivaracetam. Monitoring of phenytoin concentrations is recommended when brivaracetam is added to or discontinued from ongoing phenytoin treatment. A 21% decrease in the plasma concentration of brivaracetam has also been observed during co-administration with phenytoin. No dose adjustment is recommended for brivaracetam during concomitant phenytoin therapy.
Primidone: (Minor) Plasma concentrations of brivaracetam may decrease during co-administration with barbiturates. A 19% decrease in the plasma concentration of brivaracetam was observed during co-administration with phenobarbital; however, no dose adjustment is recommended for brivaracetam during concomitant therapy.
Protriptyline: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Rifampin: (Major) Co-administration of brivaracetam with rifampin decreases brivaracetam plasma concentrations by 45%, likely because of CYP2C19 induction. When metabolized, brivaracetam undergoes hydroxylation that is mediated by CYP2C19. The dose of brivaracetam should be increased by up to 100% in patients in patients taking concomitant rifampin.
Secobarbital: (Minor) Plasma concentrations of brivaracetam may decrease during co-administration with barbiturates. A 19% decrease in the plasma concentration of brivaracetam was observed during co-administration with phenobarbital; however, no dose adjustment is recommended for brivaracetam during concomitant therapy.
St. John's Wort, Hypericum perforatum: (Major) Co-administration of brivaracetam with St. John's Wort, Hypericum perforatum may decrease brivaracetam plasma concentrations, likely because of CYP2C19 induction by St. John's Wort. When metabolized, brivaracetam undergoes hydroxylation that is mediated by CYP2C19. During drug interaction studies, co-administration of brivaracetam with rifampin, another CYP2C19 inducer, decreased brivaracetam plasma concentrations by 45%. The dose of brivaracetam should be increased by up to 100% in patients in patients taking concomitant rifampin, and similar consideration may be warranted when brivaracetam is used with St. John's Wort.
Trazodone: (Moderate) Trazodone can lower the seizure threshold of anticonvulsants, although the overall risk is low at therapeutic doses. Patients may require increased concentrations of anticonvulsants to achieve equivalent effects if trazodone is added. Finally, drowsiness may be additive between trazodone and other anticonvulsants.
Tricyclic antidepressants: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Trimipramine: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
The exact mechanism by which brivaracetam produces anticonvulsant activity is not known. Anticonvulsant activity may reside in modulation of synaptic vesicle protein 2A (SV2A) function in the brain. Brivaracetam has highly selective and reversible affinity for SV2A, occupying 80 to 90% of SV2A within 5 to 15 minutes at clinically relevant doses, which represents maximal seizure protection in animal models. Brivaracetam has a 15- to 30-fold higher affinity for SV2A compared to levetiracetam. Additional anticonvulsant activity may be related to the modulation of voltage-dependent sodium channels.
Brivaracetam is administered orally and intravenously. Protein binding is approximately 20% or less. Brivaracetam is primarily metabolized by hydrolysis of the amide moiety to form a carboxylic acid metabolite and secondarily by CYP2C19 mediated hydroxylation on the propyl side chain to form a hydroxy metabolite. An additional hydroxy acid metabolite is formed by hydrolysis of the amide moiety on the hydroxy metabolite or hydroxylation of the propyl side chain on the carboxylic acid metabolite. None of the 3 metabolites are pharmacologically active. Genetic variations in CYP2C19 may influence brivaracetam blood concentrations, as increases of 22% and 42% have been observed in individuals with one or both mutated alleles. Brivaracetam is excreted renally with less than 10% excreted unchanged in the urine. Fecal excretion accounts for less than 1% of the dose. Brivaracetam plasma half-life is approximately 9 hours. Brivaracetam oral tablets, oral solution, and intravenous injection may be used interchangeably.
Affected cytochrome P450 isoenzymes: CYP2C19
Brivaracetam is metabolized by CYP2C19. A drug interaction study with rifampin demonstrated a 45% decrease in brivaracetam plasma concentrations, likely secondary to CYP2C19 induction. Concomitant administration with CYP inhibitors or transporter inhibitors is unlikely to significantly influence brivaracetam exposure.
-Route-Specific Pharmacokinetics
Oral Route
Brivaracetam is rapidly and almost completely absorbed after administration. The median Tmax for tablets administered without food is 1 hour (range, 0.25 to 3 hours). Administration with a high-fat meal slows absorption but does not change the extent of absorption. When a 50 mg tablet was given with a high-fat meal, Tmax was delayed by 3 hours and Cmax was decreased by 37%; however, the AUC was essentially unchanged (decreased by 5%).
-Special Populations
Hepatic Impairment
Brivaracetam exposure is increased with hepatic impairment. When compared to matched healthy controls, adult subjects with hepatic cirrhosis with Child-Pugh scores A, B, and C had increases in brivaracetam exposure of 50%, 57%, and 59%, respectively. The effect of hepatic impairment on brivaracetam pharmacokinetics in pediatric patients is expected to be comparable to the effect observed in adults.
Renal Impairment
The plasma AUC of brivaracetam increased by 21% in subjects with severe renal impairment (creatinine clearance less than 30 mL/minute/1.73 m2) compared to healthy controls. Brivaracetam has not been studied in patients undergoing hemodialysis.
Pediatrics
A weight-based dosing regimen is necessary to achieve brivaracetam exposures in infants, children, and adolescents that are similar to those observed in adults. Estimated plasma clearance is 1.09 L/hour in pediatric patients weighing 11 kg, 1.81 L/hour in pediatric patients weighing 20 kg, and 3.11 L/hour in pediatric patients weighing 50 kg, compared to 3.58 L/hour in adult patients (70 kg body weight).
Geriatric
In geriatric subjects with creatinine clearance of 53 to 98 mL/minute/1.73 m2, the plasma half-life of brivaracetam was reduced to 7.9 hours in patients 65 to 75 years and remained unchanged at 9.3 hours in patients 75 years and older.
Gender Differences
No differences were observed in brivaracetam pharmacokinetics between males and females.
Ethnic Differences
No significant differences were observed in brivaracetam pharmacokinetics between Caucasian and non-Caucasian patients.