CLASSES

Anticonvulsants, SV2A Inhibitors

DEA CLASS

Rx, schedule V

DESCRIPTION

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

COMMON BRAND NAMES

BRIVIACT

HOW SUPPLIED

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

DOSAGE & INDICATIONS

MAXIMUM DOSAGE

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.

DOSING CONSIDERATIONS

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.

STORAGE

BRIVIACT:
- Store at 77 degrees F; excursions permitted to 59-86 degrees F

CONTRAINDICATIONS / PRECAUTIONS

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 elderly patient should be cautious, usually starting at the low end of the dosing range. According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric patients 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.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; the use of any anticonvulsant for any condition should be based on confirmation of the condition and its potential cause(s). Determine effectiveness and tolerability by evaluating symptoms, and use these as the basis for dosage adjustment for most patients. Therapeutic drug monitoring is not required or available for most anticonvulsants. Serum medication concentrations (when available) may assist in identifying toxicity. Monitor the treated patient for drug efficacy and side effects. Anticonvulsants can cause a variety of side effects; some adverse reactions can increase the risk of falls. When an anticonvulsant is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity as outlined in the OBRA guidelines.[60742]

There are no adequate data on the developmental risks associated with brivaracetam use in pregnant women. 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 patients who receive brivaracetam to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 1-888-233-2334 to enroll in the registry.

There are no data describing the presence of brivaracetam in human milk, the effects on the breast-fed infant, or the effects on milk production. In lactating rats, brivaracetam was excreted in milk and quickly reached concentrations similar to those in plasma. 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.[60593]

ADVERSE REACTIONS

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

DRUG INTERACTIONS

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.
Aspirin, ASA; Butalbital; 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.
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.
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.

PREGNANCY AND LACTATION

There are no adequate data on the developmental risks associated with brivaracetam use in pregnant women. 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 patients who receive brivaracetam to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 1-888-233-2334 to enroll in the registry.

There are no data describing the presence of brivaracetam in human milk, the effects on the breast-fed infant, or the effects on milk production. In lactating rats, brivaracetam was excreted in milk and quickly reached concentrations similar to those in plasma. 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.

MECHANISM OF ACTION

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.

PHARMACOKINETICS

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.