Brivaracetam (Briviact, UCB)
Indication and Clinical Profile9,10
Brivaracetam was approved as an adjunctive therapy with other medications to treat partial-onset seizures in patients aged ≥16 years. Epilepsy, one of the most common central nervous system (CNS) pathologies, may be caused by stroke, infection, tumors, traumatic brain injury, or abnormal brain development. In many patients, the specific cause is not known. Approximately 5.1 million people in the United States have a history of epilepsy, and approximately 2.9 million have active epilepsy. Patients have different responses to the various seizure medications available, and brivaracetam offers patients a new treatment option.
FDA approval of brivaracetam was based on three phase III trials (studies 1–3). These multicenter, doubleblind, controlled trials enrolled 1,550 patients with partial-onset seizures not adequately controlled with one or two concomitant antiepileptic therapies. All trials had an 8-week baseline period to identify patients who had at least eight partial-onset seizures. The baseline period was followed by a 12-week treatment period. Study 1 compared brivaracetam dosages of 50 mg and 100 mg per day with placebo; study 2 compared a dosage of 50 mg per day with placebo, and study 3 compared dosages of 100 mg and 200 mg per day with placebo. Compared with placebo, brivaracetam demonstrated statistically significant reductions (19.5%, 24.4%, and 24.0% for 50, 100, and 200 mg/day, respectively) in partial-onset seizure frequency per 28 days (P <.01). The proportion of patients with a ≥50% reduction in partial-onset seizure frequency was 34.2% (50 mg/day), 39.5% (100 mg/day), and 37.8% (200 mg/day), respectively, versus 20.3% for placebo (P <.01 for all arms).
Pharmacology and Pharmacokinetics9,10
Brivaracetam is the 4-n-propyl derivative of the previously approved anticonvulsant levetiracetam (Keppra; Figure 3). The precise mechanism by which brivaracetam exerts its therapeutic activity is not known; however, the drug is bound with high affinity and selectivity by the synaptic vesicle protein 2A in various regions of the CNS, and this appears to contribute to the anticonvulsant effect. In animal models, brivaracetam is approximately 10 times more potent than levetiracetam in seizure prevention.
Brivaracetam is rapidly and completely absorbed after oral administration, providing peak levels within an hour. Administration with a high-fat meal slows the rate, but not the extent, of absorption. The drug is rapidly and evenly distributed to most tissues and is minimally bound by plasma proteins. Brivaracetam is metabolized primarily by amidase-mediated hydrolysis to the carboxylic acid and secondarily by CYP2C19 hydroxylation of the propyl side chain. Both metabolites are inactive. Therefore, to minimize brivaracetam overexposure and toxicity, dose reduction may be necessary in patients who are poor metabolizers owing to mutated CYP2C19 alleles, patients receiving concurrent CYP2C19 inhibitor therapy, and patients with hepatic disease. More than 95% of the dose is eliminated in the urine, primarily as metabolites. The terminal plasma half-life is about 9 hours.
Adverse Reactions and Drug Interactions9,10
The most common side effects associated with brivaracetam in clinical trials included drowsiness, dizziness, fatigue, nausea, and vomiting. This drug must be dispensed with a patient medication guide, which provides important information about brivaracetam's use and risks. As is true of all drugs used to treat epilepsy, the most serious risks include suicidal thoughts, suicide attempts, feelings of agitation, new or worsening depression, aggression, and panic attacks. Rarely, patients may exhibit severe allergic reactions associated with swelling of the lips, eyelids, or tongue with or without difficulty breathing. Caution is advised in pregnancy because brivaracetam has been shown to cause fetal harm in animal models. Abrupt withdrawal of brivaracetam should be avoided in order to minimize the risk of increased seizure frequency and status epilepticus.
Brivaracetam does not produce clinically significant inhibition or induction of any of the primary CYP isozymes or major transporters in human tissues, and therefore it is unlikely to alter the metabolism or transport of other substrate drugs administered concurrently. Drugs that are CYP2C19 inducers (e.g., rifampin, phenytoin, and phenobarbital) can reduce plasma concentrations of brivaracetam by approximately 20% to 40%, and coadministration with rifampin may require a doubling of the brivaracetam dose. CYP2C19 inhibitors can cause modest plasma increases in brivaracetam plasma levels.
Dosage and Administration9,10
Brivaracetam is supplied in three formulations: tablet (10, 25, 50, 75, and 100 mg), oral solution (10 mg/mL), and injection for IV administration. The recommended oral starting dosage is 50 mg twice daily (100 mg/day). Based on individual patient tolerability and therapeutic response, the dosage may be adjusted down to 25 mg twice daily (50 mg/day) or up to 100 mg twice daily (200 mg/day). For all stages of hepatic impairment, the recommended starting dosage is 25 mg twice daily, with a maximum dosage of 75 mg twice daily. When oral dosing is temporarily not feasible, brivaracetam may be given parenterally in the same dosages employed for oral administration. When a patient discontinues brivaracetam, the drug should be withdrawn gradually.
US Pharmacist. 2016;41(10):30-36. © 2016 Jobson Publishing