Intravenous Partial seizures with or without secondary generalisation
Adult: Alternative when oral use is temporarily not feasible: As adjunctive therapy: Initially, 50 mg or 100 mg daily based on the need for seizure control. Doses may be adjusted to 50-200 mg daily according to response and tolerability. All doses must be given in 2 equally divided doses (at least 12 hours apart) via bolus inj or infusion over 15 minutes for up to 4 days. Dosage and treatment recommendations may vary between countries (refer to specific product guidelines). Child: Alternative when oral use is temporarily not feasible: As adjunctive therapy: ≥2 years weighing 10-<20 kg: Initially, 1 mg/kg daily up to 2.5 mg/kg daily based on the need for seizure control. Doses may be adjusted to 1-5 mg/kg daily according to response and tolerability. Maintenance: 2.5 mg/kg daily; 20 kg-<50 kg: Initially, 1 mg/kg daily up to 2 mg/kg daily based on the need for seizure control. Doses may be adjusted to 1-4 mg/kg daily according to response and tolerability. Maintenance: 2 mg/kg daily; ≥50 kg: Initially, 50 mg or 100 mg daily based on the need for seizure control. Doses may be adjusted to 50-200 mg daily according to response and tolerability. Maintenance: 100 mg daily. All doses must be given in 2 equally divided doses (at least 12 hours apart) via bolus inj or infusion over 15 minutes for up to 4 days. Dosage and treatment recommendations may vary between countries (refer to specific product guidelines).
Oral Partial seizures with or without secondary generalisation
Adult: As adjunctive therapy: Initially, 50 mg or 100 mg daily based on the need for seizure control. Doses may be adjusted to 50-200 mg daily according to response and tolerability. All doses must be given in 2 equally divided doses, at least 12 hours apart. Dosage and treatment recommendations may vary between countries (refer to specific product guidelines). Child: As adjunctive therapy: ≥2 years weighing 10-<20 kg: Initially, 1 mg/kg daily up to 2.5 mg/kg daily based on the need for seizure control. Doses may be adjusted to 1-5 mg/kg daily according to response and tolerability. Maintenance: 2.5 mg/kg daily; 20 kg-<50 kg: Initially, 1 mg/kg daily up to 2 mg/kg daily based on the need for seizure control. Doses may be adjusted to 1-4 mg/kg daily according to response and tolerability. Maintenance: 2 mg/kg daily; ≥50 kg: Initially, 50 mg or 100 mg daily based on the need for seizure control. Doses may be adjusted to 50-200 mg daily according to response and tolerability. Maintenance: 100 mg daily. All doses must be given in 2 equally divided doses, at least 12 hours apart. Dosage and treatment recommendations may vary between countries (refer to specific product guidelines).
Special Patient Group
Patients taking concomitant rifampicin: Increase brivaracetam dose by up to 100%.
Pharmacogenomics:
Brivaracetam is primarily metabolised via hydrolysis by hepatic and extrahepatic amidases to form inactive carboxylic acid metabolite, and secondarily via hydroxylation of the propyl side chain mainly mediated by CYP2C19 isoenzyme to form inactive hydroxy metabolite.
Individuals who have a certain CYP2C19 genetic variation, known as CYP2C19 poor metabolisers, may experience higher exposure to brivaracetam. The prevalence of CYP2C19 poor metabolisers is approx 2% in Caucasians, 4% in African-Americans, and 14% in Chinese ancestry. Genetic testing may be considered.
CYP2C19 poor metabolisers
According to studies, patients may have decreased production of the hydroxy metabolite by 2-fold or 10-fold, while the blood level of brivaracetam itself is increased by 22% or 42% respectively, in individuals with 1 or both mutated alleles. CYP2C19 poor metabolisers may require dose reduction as they may be at increased risk of adverse reactions.
Renal Impairment
ESRD undergoing dialysis: Not recommended.
Hepatic Impairment
Mild to severe (Child-Pugh classes A, B, and C): Adults and children weighing ≥50 kg: Initially, 50 mg daily. Max: 150 mg daily; children 20 kg-<50 kg: Initially, 1 mg/kg daily. Max: 3 mg/kg daily; children 10-<20kg: Initially, 1 mg/kg daily. Max: 4 mg/kg daily. All doses are given in 2 equally divided doses, at least 12 hours apart. Dosage recommendations may vary between countries (refer to specific product guidelines).
Administration
May be taken with or without food. Oral soln does not need to be diluted before swallowing. May be administered via nasogastric tube or gastrostomy tube.
Reconstitution
IV infusion: May be mixed with compatible diluents (e.g. 0.9% NaCl solution for inj, Lactated Ringer’s solution for inj, or 5% dextrose in water).
Contraindications
Hypersensitivity to brivaracetam or other pyrrolidone derivatives.
Special Precautions
CYP2C19 poor metabolisers. Avoid abrupt withdrawal. Not recommended in patients with ESRD undergoing dialysis. Hepatic impairment. Children. Pregnancy and lactation.
Adverse Reactions
Significant: Suicidal ideation or behaviour, psychiatric symptoms (e.g. psychosis, paranoia, hallucinations, behavioural symptoms), CNS depression (e.g. dizziness, somnolence, impaired coordination, ataxia, abnormal gait); haematologic abnormalities (e.g. decreased WBC count, neutrophil count). Ear and labyrinth disorders: Vertigo. Eye disorders: Nystagmus. Gastrointestinal disorders: Nausea, vomiting, constipation; dysgeusia (IV). General disorders and administration site conditions: Fatigue; infusion site pain (IV). Infections and infestations: Influenza. Metabolism and nutrition disorders: Decreased appetite. Nervous system disorders: Sedation, balance disorder, convulsion. Psychiatric disorders: Depression, anxiety, insomnia, irritability, aggression, agitation. Respiratory, thoracic and mediastinal disorders: Upper respiratory tract infections, cough. Potentially Fatal: Hypersensitivity reactions, including bronchospasm, angioedema, and multiorgan hypersensitivity syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS).
IV/PO: Z (Insufficient data to conclude its safety and risk during pregnancy. Use only when benefits outweigh risks.)
Patient Counseling Information
This drug may cause dizziness, somnolence, or impaired coordination; if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor CBC with differential, LFTs, and renal function tests. Closely monitor for signs and symptoms of psychosis, depression, and suicidality (at baseline and as clinically indicated).
Overdosage
Symptoms: Somnolence, dizziness, nausea, vertigo, balance disorder, fatigue, irritability, anxiety, insomnia, aggression, depression, and suicidal ideation. Management: Symptomatic and supportive treatment. Ensure an adequate airway, oxygenation, and ventilation. Monitor vital signs and cardiac rate and rhythm.
Drug Interactions
Reduced systemic exposure when co-administered with rifampicin. Plasma concentration may be increased with strong CYP2C19 inhibitors (e.g. fluconazole, fluvoxamine). Decreased plasma concentration with strong enzyme-inducing antiepileptic drugs (e.g. carbamazepine, phenytoin, phenobarbital).
Food Interaction
High-fat meals may delay the rate but not the extent of absorption. May increase the effects of alcohol on psychomotor function, attention, and memory. Systemic exposure may be reduced by St. John's wort.
Action
Description: Mechanism of Action: Brivaracetam is an analogue of levetiracetam. The exact mechanism for its anticonvulsant effect is unknown; however, it displays a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain, which may contribute to the anticonvulsant activity. Pharmacokinetics: Absorption: Rapidly and completely absorbed following oral administration. Delayed rate of absorption by 3 hours with a high-fat meal. Absolute bioavailability: Approx 100% (oral). Time to peak plasma concentration: Fasted state: Approx 1 hour (range: 0.25-3 hours). Distribution: Rapidly and evenly distributed into most body tissues. Volume of distribution: 0.5 L/kg. Plasma protein binding: Approx 20%. Metabolism: Metabolised primarily via hydrolysis of the amide moiety by hepatic and extrahepatic amidase to form carboxylic acid metabolite, and secondarily via hydroxylation of the propyl side chain mainly by CYP219 isoenzymes to form hydroxy metabolite. Both metabolites undergo further metabolism into a common hydroxylated acid. All 3 metabolites are inactive. Excretion: Mainly via urine (>95%; <10% as unchanged drug); faeces (<1%). Elimination half-life: Approx 9 hours.
Chemical Structure
Brivaracetam Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 9837243, Brivaracetam. https://pubchem.ncbi.nlm.nih.gov/compound/9837243. Accessed Aug. 26, 2022.
Storage
Tab: Store between 15-30°C. Oral solution/IV inj or infusion: Store between 15-30°C. Do not freeze.
N03AX23 - brivaracetam ; Belongs to the class of other antiepileptics.
References
Dean L. Brivaracetam Therapy and CYP2C19 Genotype. In: Pratt VM, Scott SA, Pirmohamed M, et al. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012-. 2018 May. Accessed 19/08/2022. PMID: 29763212Annotation of EMA Label for Brivaracetam and CYP2C19. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 19/08/2022.Annotation of FDA Label for Brivaracetam and CYP2C19. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 01/08/2022.Anon. Brivaracetam. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 01/08/2022.Anon. CYP2C19 - Brivaracetam (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 19/08/2022.Briviact 10 mg/mL Oral Solution (UCB Pharma Limited). MHRA. https://products.mhra.gov.uk. Accessed 05/08/2022.Briviact 10 mg/mL Solution for Injection/Infusion (UCB Pharma Limited). MHRA. https://products.mhra.gov.uk. Accessed 01/08/2022.Briviact 50 mg Film-coated Tablets (UCB Pharma Limited). MHRA. https://products.mhra.gov.uk. Accessed 01/08/2022.Briviact Solution for Injection/Infusion 10 mg/mL (UCB Pharma [Hong Kong] Ltd.). MIMS Hong Kong. http://www.mims.com/hongkong. Accessed 19/08/2022.Briviact Tablet, Film Coated, Solution, and Injection Suspension (UCB, Inc). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 01/08/2022.Buckingham R (ed). Brivaracetam. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 01/08/2022.Joint Formulary Committee. Brivaracetam. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 01/08/2022.
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