FDA approves brivaracetam for use in partial onset seizure treatment

Kevin W. chamberlin, PharmD

Jennifer L. Marshall, PharmDOn February 18, 2016, the FDA approved Briviact (brivaracetam) by UCB, Inc., as an adjunctive therapy option, along with other primary anti-epileptics, for the treatment of partial onset seizures in patients 16 years of age and older. Epilepsy affects approximately 2-3 million people in the US and an estimated 65 million worldwide; the disease eventually progresses to a refractory state in nearly one-third of patients. Brivaracetam provides another adjunctive treatment option for partial onset seizures in patients with uncontrolled epilepsy. The drug is classified as a Schedule V controlled substance and must be dispensed with its FDA-approved medication guide.

Efficacy

Brivaracetam is an anticonvulsant with an unknown precise mechanism of action. Its anticonvulsant properties are thought to be related to its high selective affinity for synaptic vesicle protein 2A (SV2A) in the brain. Its efficacy was studied in three separate fixed-dose, randomized, double-blind, placebo-controlled, multicenter studies. A total of 1550 patients with partial onset seizures not adequately controlled with 1 or 2 concomitant antiepileptic drugs were enrolled in these studies. Patients were required to have at least 8 partial onset seizures during an 8 week baseline period prior to being initiated on a randomly assigned dose of brivaracetam or placebo for a 12 week treatment period. Brivaracetam doses studied in the three trials included 50-, 100-, and 200-mg/day, with no titration period, all of which were compared with placebo. The primary efficacy outcome for Study 1 and Study 2 was the percent reduction in 7-day partial onset seizure frequency.

In Study 1, brivaracetam 50 mg/day and 100 mg/day had a 9.5% and 17% reduction, respectively, over placebo. In Study 2, brivaracetam 50 mg/day had a 16.9% reduction over placebo. The primary efficacy outcome for Study 3 was the percent reduction in 28-day partial onset seizure frequency; brivaracetam 100 mg/day and 200 mg/day had a 25.2% and 25.7% reduction, respectively, over placebo. All data were statistically significant.

Safety

The most common adverse effects associated with brivaracetam include somnolence, sedation, dizziness, fatigue, nausea, and vomiting. Antiepileptic medications, including brivaracetam, may increase the risk of suicidal thoughts and behavior. Patients treated with brivaracetam should be closely monitored for new or worsening signs of depression, suicidal thoughts or behavior, and/or unusual changes in mood or behavior. Brivaracetam should not be abruptly discontinued due to an increased risk of seizures and status epilepticus. Brivaracetam is classified as a Pregnancy Category C.

Dosing

Brivaracetam is available as 10-, 25-, 50-, 75-, and 100 mg oral tablets, a 10 mg/mL oral solution, and a 50 mg/5 mL solution for intravenous injection. The recommended starting dose is 50 mg twice daily (100 mg/day). The dose may be titrated down to 25 mg twice daily (50 mg/day) or up to 100 mg twice daily (200 mg/day) based on patient tolerability and therapeutic response. Brivaracetam may be initiated using either oral or intravenous formulations; gradual dose escalation upon initiation is not necessary. Oral tablets may be taken without regard to meals, should be swallowed whole, taken with liquid, and should not be crushed or chewed. The intravenous formulation may be used when oral administration is not feasible and should be administered at the same dose and frequency as the oral tablets or oral solution. In clinical studies, intravenous administration was limited to 4 consecutive days of treatment. Brivaracetam intravenous solution may be administered without further dilution over 2 to 15 minutes. The manufacturer recommends increasing the dose by 100% when brivaracetam is used concomitantly with rifampin.

There are no renal dose adjustments for brivaracetam in patients with mild to severe renal impairment, but the drug should be avoided in patients with end-stage renal disease requiring dialysis as this population was not included in clinical studies. In patients with any level of hepatic impairment, including Child-Pugh classes A, B, and C, brivaracetam should be initiated at 25 mg twice daily, titrated up as necessary to a maximum of 75 mg twice daily. 

Jennifer L. Marshall is a pharmacist at John Dempsey Hospital/UConn Health, Farmington, Conn. 

Kevin W. Chamberlin is associate clinical professor and assistant department head, pharmacy practice, UConn School of Pharmacy, Storrs, CT.