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NCS Currents Sept 2016

NEUROCRITICAL CARE PHARMACY Role of New Antiepileptics in Adults with Status Epilepticus By Salia Farrokh, Pharm.D., BCPS, BCCCP Status epilepticus (SE) is a neurological emergency with high mortality rate. Although current guidelines recommend benzodiazepines as first-line agents, approximately 30-40% of patients do not respond to benzodiazepines. Other agents such as phenytoin, fosphenytoin, phenobarbital, and valproate may be utilized but their use is complicated by adverse effects and/or drug-drug interactions. This review focuses on the role of new antiepileptics in adults with SE which became available within the past 10 years such as: brivaracetam (Briviact®), clobazam (Onfi©), eslicarbazepine (Aptiom©), ezogabine (Potiga©), lacosamide (Vimpat©), perampanel (Fycompa©), rufinamide (Banzel©), and vigabatrin (Sabril©). Brivaracetam (Briviact®) Brivaracetam is a synaptic vesicle protein 2A (SV2A) ligand with greater affinity than levetiracetam for this target. It was approved in 2016 for partial-onset seizures. It is available in oral and intravenous formulations and is dosed 50 mg twice daily which could be titrated down or up to 25 mg and 100 mg twice daily respectively. For all stages of hepatic impairment, recommended starting dose is 25 mg twice daily; maximum dosage is 75 mg twice daily. In randomized placebo-controlled trials, median seizure reduction was 30.5% to 53.1% for 50 mg/day, 32.5% to 37.2% for 100 mg/day, and 35.6% for 200 mg/day. Its intravenous formulation makes it a desirable alternative for SE but there are no studies in these patients at this point. Clobazam (Onfi©) Clobazam was approved in the U.S. for adjunctive treatment of Lennox-Gastaut Syndrome in patients 2 years or older in 2011. Clobazam is a 1,5 benzodiazepine, and acts through potentiation of gamma-aminobutyric acid type A (GABA-A) receptors. It is a selective, partial agonist on GABA-A receptors, with better selectivity toward the GABA-A subunits responsible for anxiolytic and anticonvulsant effects than for those involved in sedation. The recommended adult dose is 10 mg orally daily in two divided doses which may be titrated to 20-40 mg daily in two divided doses. In 1986, a small case series in SE showed termination of status epilepticus within 15 to 31 minutes in 28 (96%) of patients. In a newer study in the U.S., successful response defined as termination of clinical and/or electrographic status epilepticus by continuous EEG monitoring within 24 hours of administration of clobazam was seen in 13 (76.5%) patients. Eslicarbazepine (Aptiom©) In 2013, the FDA approved eslicarbazepine for monotherapy or adjunctive treatment of partial onset seizures. It is thought to inhibit sodium channels. It is dosed 400-1600 mg orally daily. Currently, there is no evidence for its use in SE. Ezogabine (Potiga©) Ezogabine binds the KCNQ voltage-gated potassium channels. As a result, neuronal excitability is regulated and epileptiform activity is suppressed. It was FDA-approved in 2011 as an add-on therapy for partial-onset seizures in adults and is dosed 600 to 1200 mg orally daily. Ezogabine can cause significant urinary retention and has a black box warning for retinal abnormalities that can progress to vision loss. There are no reports of its use in SE. Lacosamide (Vimpat©) In 2009, lacosamide was approved as an adjunctive therapy for partial seizures in adults. Lacosamide works by enhancing slow sodium channels. The recommended adult dosing is 100-200 mg twice daily in oral or intravenous formulations. Multiple case reports and case series have shown that lacosamide led to termination of SE in patients unresponsive to standard therapies. Albers reported seven cases of refractory SE who were successfully treated with intravenous lacosamide as add-on therapy. In a European study, Kellinghaus retrospectively reviewed the use of intravenous lacosamide in 39 patients who had failed standard therapy except one. Seventeen (43%) patients responded to therapy while 22 patients needed further anticonvulsant treatment. In a case series that included 31 patients with status epilepticus, 25 (81%) patients responded to lacosamide. Interestingly, two patients received lacosamide as initial therapy. The overall reported success rate was 56% in these studies. Perampanel (Fycompa©) Perampanel is a first-in-class orally active, selective, non-competitive alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptor antagonist. It received FDA approval in 2012 for adjunctive treatment of focal seizures and in June 2015, for primary generalized tonic-clonic seizures. Dosing range is 4–12 mg orally daily. The first clinical experience of its use in 12 patients with refractory and superrefractory SE was reported in 2015. Perampanel was given after a median number of four antiepileptic drugs and clinical improvement was observed in two (17%) patients. Rufinamide (Banzel©) Rufinamide was approved as an adjunctive agent in Lennox- Gastaut syndrome in 2011. In vitro studies suggest that rufinamide modulates the activity of sodium channels and subsequently prolongs the inactive state of the channel. Rufinamide is dosed 400 to 800 mg/day orally in two equally divided doses to a maximum dose of 3200 mg per day but higher doses up to 4400 mg have been used in SE. Review of literature shows one successful case report with this agent when added after failure of first-line therapy and titrated up to 4400 mg/day. Vigabatrin (Sabril©) Vigabatrin was approved in 2009 as adjunctive therapy for refractory complex partial seizures in adults. It is dosed 500-1500 mg orally twice daily. Vigabatrin is only available through a mandated registry due to reports of vision loss following exposure. It is believed to act as an irreversible inhibitor of GABA transaminase and, despite evidence for its efficacy in complex partial seizures (~50% seizure reduction compared to placebo) in controlled trials, there is no evidence for its use in SE. 22


NCS Currents Sept 2016
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