Brivaracetam

Usage

• Brivaracetam is an anticonvulsant medication indicated for the treatment of partial-onset seizures in patients with epilepsy, either as monotherapy or adjunctive therapy. It is also approved for use in children aged 1 month and older.
• Pharmacological Classification: Anticonvulsant.
• Mechanism of Action: Brivaracetam exhibits a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain. While the precise mechanism by which it exerts its anticonvulsant effects is not fully elucidated, binding to SV2A is thought to modulate neurotransmitter release, thereby reducing neuronal excitability and suppressing seizure activity.

Alternate Names

• Brivaracetam is the generic name.
• Brand Name: Briviact.

How It Works

• Pharmacodynamics: Brivaracetam selectively binds to SV2A, a transmembrane glycoprotein found on synaptic vesicles in neurons. This interaction is believed to modulate neurotransmitter release and reduce neuronal hyperexcitability, contributing to its anticonvulsant effect.

• Pharmacokinetics:

  • Absorption: Brivaracetam is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations occurring within one hour. Food does not significantly affect its absorption. The bioavailability of the oral solution and tablets are similar.
  • Distribution: Brivaracetam is widely distributed throughout the body, including the brain. It has low protein binding.
  • Metabolism: Brivaracetam is primarily metabolized in the liver, mainly via hydrolysis of the amide moiety, with minimal involvement of CYP450 enzymes. This metabolic pathway distinguishes it from many other antiepileptic drugs and reduces the potential for drug-drug interactions related to CYP enzyme induction or inhibition. The major metabolite is inactive.
  • Elimination: Brivaracetam and its metabolites are primarily excreted in the urine. The elimination half-life is approximately nine hours.

• Mode of Action: Brivaracetam binds selectively to SV2A in the brain. Although the exact mechanism of anticonvulsant action is not fully understood, it is thought that brivaracetam modulates neurotransmitter release, thus decreasing neuronal excitability and suppressing seizure activity.

• Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: High and selective binding to SV2A in the brain, potentially modulating synaptic vesicle exocytosis and neurotransmitter release, especially GABA and glutamate, contributing to reduced neuronal excitability.

• Elimination Pathways: Primarily renal excretion. Less than 10% of the administered dose is excreted as unchanged drug; approximately 95% of the dose, including metabolites, is eliminated through renal excretion. Hepatic metabolism is primarily via hydrolysis and does not involve CYP450 enzymes, minimizing drug-drug interactions related to CYP isoenzymes.

Dosage

Standard Dosage

Adults (16 years and older):

• Initial dose: 50 mg twice daily (100 mg/day).
• Maintenance dose: Can be adjusted based on response and tolerability, ranging from 50 mg/day to 200 mg/day (25 mg to 100 mg twice daily).

Children (1 month to less than 16 years):

• Dosage is weight-based:
  • < 11 kg: Initial: 0.75-1.5 mg/kg twice daily; Maintenance: 0.75-3 mg/kg twice daily (maximum 4.5 mg/kg twice daily).
  • 11 to < 20 kg: Initial: 0.5-1.25 mg/kg twice daily; Maintenance: 0.5-2.5 mg/kg twice daily (maximum 2 mg/kg twice daily).
  • 20 to < 50 kg: Initial: 0.5-1 mg/kg twice daily; Maintenance: 0.5-2 mg/kg twice daily (maximum 1.5 mg/kg twice daily).
  • ≥ 50 kg: Initial: 25-50 mg twice daily; Maintenance: 25-100 mg twice daily.
• Safety and efficacy have not been established in children younger than 1 month.

Special Cases:

• Elderly Patients: Initiate at the lower end of the dosing range (50 mg/day), with careful titration based on tolerability and response due to potential age-related decline in hepatic, renal, or cardiac function.
• Patients with Renal Impairment (Mild to Moderate): No dosage adjustment necessary. Use with caution in patients with End-Stage Renal Disease (ESRD) due to lack of data. Generally not recommended for individuals undergoing dialysis.
• Patients with Hepatic Dysfunction:
  • Adults and children ≥ 50 kg: Initial: 25 mg twice daily (50 mg/day); Maximum: 75 mg twice daily (150 mg/day). Pediatric dosing with hepatic impairment should follow specific weight-based recommendations. Dosage adjustment recommended for all stages.
• Patients with Comorbid Conditions: Exercise caution and adjust dosage based on individual patient needs. Consider potential drug interactions and effects on other medical conditions.

Clinical Use Cases

• Intubation/Surgical Procedures/Mechanical Ventilation/ICU Use/Emergency Situations: Brivaracetam injection can be used when oral administration is temporarily not feasible. Administer intravenously at the same dosage and frequency as the oral formulation. Clinical trials have limited IV administration to a maximum of four consecutive days.

Dosage Adjustments:

• Adjust dosage according to individual patient response and tolerability, considering renal or hepatic dysfunction, and concomitant medications. If co-administered with the strong CYP3A4 inducer rifampin, double the brivaracetam dose.

Side Effects

Common Side Effects:

• Somnolence (drowsiness).
• Dizziness.
• Fatigue.
• Nausea.
• Vomiting.
• Ataxia (loss of balance/coordination)
• Tremor

Rare but Serious Side Effects:

• Suicidal ideation and behavior.
• Severe allergic reactions (angioedema, bronchospasm).
• Neutropenia.
• Psychosis.
• Severe skin rashes (Stevens-Johnson Syndrome).
• Hepatotoxicity.

Long-Term Effects:

• Some side effects, like fatigue or dizziness, may persist with long-term use. Periodic monitoring of blood counts and liver function is advisable during prolonged therapy.

Adverse Drug Reactions (ADR):

• Angioedema, bronchospasm, and anaphylaxis require immediate medical intervention. Psychiatric adverse reactions, including psychosis or suicidality, should also prompt immediate attention.

Contraindications

• Hypersensitivity to brivaracetam or other pyrrolidone derivatives.

Drug Interactions

• Rifampin (strong CYP3A4 inducer): Double the brivaracetam dose.
• Carbamazepine: May increase levels of carbamazepine-epoxide, an active metabolite of carbamazepine.
• Alcohol: Can enhance CNS depressant effects.
• Other CNS depressants (e.g., benzodiazepines, opioids): Additive CNS depressant effects.
• Oral Contraceptives : Brivaracetam at higher doses may reduce exposure to certain oral contraceptives, so use with caution and consider alternative birth control if needed.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Category C (Caution advised; consider benefits vs. risks). Brivaracetam can cross the placenta. Animal studies have demonstrated potential adverse effects on fetal development. Use during pregnancy only if clearly needed and benefits outweigh potential risks.
• Breastfeeding: Brivaracetam is present in breast milk. Consider risks vs benefits of breastfeeding while taking brivaracetam. Monitor infant for drowsiness and adequate weight gain.

Drug Profile Summary

• Mechanism of Action: Selectively binds to SV2A, modulating neurotransmitter release and reducing neuronal excitability.
• Side Effects: Somnolence, dizziness, fatigue, nausea, suicidal ideation, angioedema, psychosis.
• Contraindications: Hypersensitivity to brivaracetam or other pyrrolidone derivatives.
• Drug Interactions: Rifampin, carbamazepine, alcohol, other CNS depressants, oral contraceptives.
• Pregnancy & Breastfeeding: Use with caution. Potential fetal risks, excreted in breast milk.
• Dosage: Adults: 50-200 mg/day divided twice daily. Pediatrics: weight-based dosing.
• Monitoring Parameters: Liver function tests (LFTs), Complete Blood Count (CBC), and monitor for psychiatric symptoms, especially during initial therapy.

Popular Combinations

• Often used in combination with other antiepileptic drugs like levetiracetam, lamotrigine, or valproate when monotherapy is inadequate for seizure control.

Precautions

• General Precautions: Assess for suicidal ideation and psychiatric symptoms at baseline and periodically throughout treatment. Monitor for hypersensitivity reactions and neurological adverse reactions.
• Specific Populations: See dosage adjustments for renal/hepatic impairment, elderly, and pediatric patients. Pregnancy: Weigh benefits vs. risks; adequate contraception advised. Breastfeeding: Monitor infant for adverse effects.
• Lifestyle Considerations: Avoid alcohol. Caution with driving or operating machinery until effects are known.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Brivaracetam?

A: Adults: Initial 50 mg twice daily, adjustable to 50-200 mg/day. Pediatrics: Weight-based dosing (see detailed dosage section above).

Q2: How should Brivaracetam be administered?

A: Orally, with or without food, in two equally divided doses approximately 12 hours apart. Intravenous administration is an alternative if oral intake is temporarily not feasible.

Q3: What are the common side effects of Brivaracetam?

A: Common side effects include drowsiness, dizziness, fatigue, nausea, and vomiting.

Q4: What are the serious side effects of Brivaracetam?

A: Suicidal thoughts or actions, allergic reactions (angioedema, bronchospasm), and psychiatric adverse reactions. Contact a physician if these occur.

Q5: Can Brivaracetam be used during pregnancy?

A: It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Q6: Can Brivaracetam be used during breastfeeding?

A: It is excreted in human breast milk. A decision must be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Q7: Does Brivaracetam interact with other medications?

A: Yes. It can interact with rifampin, carbamazepine, and other CNS depressants. Be sure to inform your doctor about all medications you are taking.

Q8: What should I do if I miss a dose of Brivaracetam?

A: Take the missed dose as soon as you remember. Take your next dose at the regularly scheduled time. Do not double up on doses.

Q9: How long does it take for Brivaracetam to work?

A: The onset of anticonvulsant activity may vary, with some patients experiencing improvement relatively soon after initiating treatment, while others may require dosage adjustments and longer periods to observe optimal effects.

Q10: Can Brivaracetam be used as monotherapy?

A: Yes, brivaracetam is approved for use as both monotherapy and adjunctive therapy in the treatment of partial-onset seizures. The choice between monotherapy and adjunctive therapy depends on the individual patient’s characteristics, including their seizure type, prior treatment history, and comorbidities.