Drug information of Brivaracetam

Brivaracetam

Drug group: Anticonvulsants

Brivaracetam is an anti-epileptic drug, also called an anticonvulsant. Brivaracetam is used to treat partial onset seizures in people with epilepsy.

Mechanism of effect

Exact mechanism unknown.

Displays a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain, which may contribute to the anticonvulsant effect.

Pharmacodynamic

Brivaracetam binds SV2A with high affinity . SV2A is known to play a role in epileptogenesis through modulation of synaptic GABA release . It is thought that brivaracetam exerts its anti-epileptogenic effects through its binding to SV2A. Brivaracetam is also known to inhibit Na+ channels which may also contribute to its anti-epileptogenic action .

Pharmacokinetics

-Absorption: Highly permeable and is rapidly and almost completely absorbed after PO administration

-Peak plasma time: 1 hr (without food); slower absorption with a high-fat meal

-Protein bound: ≤20%

-Vd: 0.5 L/kg

-Metabolism:

Primarily metabolized by hydrolysis of the amide moiety to form the corresponding carboxylic acid metabolite and is mediated by hepatic and extra-hepatic amidase.

Secondarily metabolized by hydroxylation on the propyl side chain to form the hydroxy metabolite that is mediated primarily by CYP2C19.

An additional hydroxy acid metabolite is created by hydrolysis of the amide moiety on the hydroxy metabolite or hydroxylation of the propyl side chain on the carboxylic acid metabolite (mainly by CYP2C9).

The 3 metabolites are not pharmacologically active.

-Half-life: 9 hr

-Excretion:

Urine (>95%); feces (<1%)

<10% of the dose is excreted unchanged in the urine

34% of the dose is excreted as the carboxylic acid metabolite in urine

Drug indications

Partial-Onset Seizures

Dosage

Adult
50 mg PO/IV q12hr initially; based on individual patient tolerability and therapeutic response, adjust dose between to 25-100 mg PO/IV BID (50-200 mg/day).

In Hepatic impairment All stages: Decrease starting dose to 25 mg BID and do not exceed 75 mg BID (150 mg/day).

PEDIATRIC

-Tablets or oral solution:

Indicated for partial-onset seizures in children and adolescents ≥4 years

-<4 years: Safety and efficacy not established

-4 to <16 years

11 to <20 kg: 0.5-1.25 mg/kg PO BID (1-2.5 mg/kg/day) initially; based on individual patient tolerability and therapeutic response, adjust dose between to 0.5-2.5 mg/kg PO BID (1-5 mg/kg/day)

20 to <50 kg: 0.5-1 mg/kg PO BID (1-2 mg/kg/day) initially; based on individual patient tolerability and therapeutic response, adjust dose between to 0.5-2 mg/kg PO BID (1-4 mg/kg/day)

≥50 kg: 25-50 mg PO BID (50-100 mg/day) initially; based on individual patient tolerability and therapeutic response, adjust dose between to 25-100 mg PO BID (50-200 mg/day)

-≥16 years

50 mg PO BID (100 mg/day) initially; based on individual patient tolerability and therapeutic response, adjust dose between to 25-100 mg PO BID (50-200 mg/day)

-Injection

Indicated for partial-onset seizures in adolescents ≥16 years with epilepsy

Injection may be used for patients when oral administration is temporarily not feasible

-<16 years: Safety and efficacy not established

-≥16 years: 50 mg IV q12hr initially; based on individual patient tolerability and therapeutic response, adjust dose between to 25-100 mg IV BID (50-200 mg/day)

Clinical study experience with injection is limited to 4 consecutive days of treatment.

-Hepatic impairment in PEDIATRIC

-Starting dose adjustments

11 to <50 kg: Start at 0.5 mg/kg PO BID (1 mg/kg/day)

20 to <50 kg: Start at 1.5 mg/kg PO BID (3 mg/kg/day)

≥50 kg: Start at 25 mg PO BID (50 mg/day)

-Maximum dose with hepatic impairment

11 to <20 kg: Not to exceed 2 mg/kg PO BID (4 mg/kg/day)

20 to <50 kg: 1.5 mg/kg PO BID (3 mg/kg/day)

≥50 kg: Not to exceed 75 mg PO BID (150 mg/day)

Drug contraindications

Hypersensitivity

Hypersensitivity; bronchospasms and angioedema have occurred

Side effects

Angioedema , vertigo , asthenia , neutropenia , decreased WBC , Hypersensitivity , difficulty urinating , pain at site of injection , tiredness , indigestion

Drowsiness , fatigue , hypersomnia ,lethargy , malaise , sedation ,abnormal gait , ataxia , dizziness , equilibrium disturbance , vertigo , psychiatric disturbance,Asthenia ,Nystagmus ,Euphoria , infusion site pain , intoxicated feeling , irritability ,Nausea , vomiting ,dysgeusia , constipation ,Decreased white blood cell count ,Suicidal ideation,Hypersensitivity reaction,Angioedema, bronchospasm, decreased neutrophils

metoclopramide intranasal-selinexor-brexanolone-carbamazepine-cenobamate-deutetrabenazine-esketamine intranasal-ethanol-lasmiditan-lemborexant-levetiracetam-midazolam intranasal-phenobarbital-phenytoin-rifampin-rucaparib-stiripentol

Alerts

- Antiepileptic drugs increase the risk of suicidal behavior and ideation

- May cause psychiatric adverse reactions, including nonpsychotic and psychotic symptoms;

- May cause somnolence and fatigue (dose-dependent), dizziness, and disturbance in gait or coordination.

- Hypersensitivity reactions reported, including bronchospasm and angioedema.

- CYP2C19 poor metabolizers and patients using inhibitors of CYP2C19 may require dose reduction.Strong CYP2C19 inducers (eg, rifampin) require dose increase.

- Coadministration with carbamazepine may increase exposure to carbamazepine-epoxide, the active metabolite of carbamazepine.

- Because brivaracetam can increase plasma concentrations of phenytoin, monitor phenytoin levels in patients when concomitant brivaracetam is added to or discontinued from ongoing phenytoin therapy.

-Hematologic effects: May cause hematologic abnormalities; significant decreased white blood cell count and decreased neutrophil count have been reported.

 

Points of recommendation

- monitor for the emergence or worsening of depression, unusual changes in mood or behavior, or suicidal thoughts, behavior, or self-harm; 

- If discontinued, withdraw drug gradually because of the risk of increased seizure frequency and status epilepticus; if withdrawal is needed because of a serious adverse event, consider rapid discontinuation.

- Injection may be used for patients when oral administration is temporarily not feasible; clinical study experience with injection is limited to 4 consecutive days of treatment.

- Coadministration with rifampin: Increase dose by 100% (ie, double dose)

Pregnancy level

HAVE NOT BEEN ESTABLISHED

No adequate and well-controlled studies in pregnant women.

In animal studies, brivaracetam produced evidence of developmental toxicity at plasma exposures greater than clinical exposure.

Breast feeding warning

Unknown if distributed in human breast milk.

Studies in rats have shown excretion in milk.

Because many drugs are excreted into human milk, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Drug forms

Briviact

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