BRIVIACT

Anticonvulsants, SV2A Inhibitors

suicidal ideation / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
bronchospasm / Rapid / Incidence not known

ataxia / Delayed / 3.0-3.0
nystagmus / Delayed / 3.0-3.0
constipation / Delayed / 2.0-2.0
leukopenia / Delayed / 1.8-1.8
neutropenia / Delayed / 0.3-0.3
euphoria / Early / 3.0
depression / Delayed / Incidence not known
hallucinations / Early / Incidence not known
psychosis / Early / Incidence not known

drowsiness / Early / 16.0-16.0
dizziness / Early / 12.0-12.0
fatigue / Early / 9.0-9.0
vomiting / Early / 5.0-5.0
nausea / Early / 5.0-5.0
irritability / Delayed / 3.0-3.0
dysgeusia / Early / 3.0
injection site reaction / Rapid / 3.0
vertigo / Early / Incidence not known
lethargy / Early / Incidence not known
asthenia / Delayed / Incidence not known
malaise / Early / Incidence not known
restlessness / Early / Incidence not known
anxiety / Delayed / Incidence not known
agitation / Early / Incidence not known
paranoia / Early / Incidence not known
emotional lability / Early / Incidence not known
hyperactivity / Early / Incidence not known
anorexia / Delayed / Incidence not known

BRIVIACT

Rx, schedule V

2-pyrrolidine derivative and levetiracetam analog
Used for partial onset seizures in patients 1 month and older
Increased risk of suicidal ideation and behavior

50 mg PO twice daily. Adjust dosage to 25 to 100 mg PO twice daily based on clinical response and tolerability.

50 mg PO twice daily. Adjust dosage to 25 to 100 mg PO twice daily based on clinical response and tolerability.

25 to 50 mg PO twice daily. Adjust dosage up to 100 mg PO twice daily based on clinical response and tolerability.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.[60593]

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.

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.
Butabarbital: (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.
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.
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.
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.
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.
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.

BRIVIACT Intravenous Inj Sol: 1mL, 10mg
BRIVIACT Oral Sol: 1mL, 10mg
BRIVIACT Oral Tab: 10mg, 25mg, 50mg, 75mg, 100mg

200 mg/day PO or IV.

200 mg/day PO or IV.

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.

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.

weighing 11 to 19 kg: 5 mg/kg/day PO or IV.
weighing less than 11 kg: 6 mg/kg/day PO or IV.

Safety and efficacy have not been established.

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.

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%).

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.