Ezogabine was approved by the Food and Drug Administration (FDA) in June of 2011. This article reviews clinically significant aspects of this new drug including: the FDA-approved indications, mechanism of action, administration, drug interactions, adverse effects, clinical trial evidence, innovative properties and place in therapy.

JR is a 33 year-old patient with complex partial seizures with secondary generalization who arrives to your medication management clinic. He has a significant history of anticonvulsant use and polytherapy, to which he has not responded optimally. JR is currently taking divalproex 1250 mg twice daily and topiramate 200 mg twice daily and continues to have monthly seizure episodes. He is highly motivated to become seizure-free. His neurologist is considering augmentation, but requests your expertise for an adjunctive agent. What is a rational adjunctive option for JR that may help provide better seizure control?

Potiga™ (ezogabine) is a newly approved anticonvulsant indicated for adjunctive treatment of partial-onset epilepsy in adults.1 Ezogabine is known as Trobalt™ or by the generic name retigabine in the European Union and elsewhere.2 Ezogabine was FDA- approved on June 10, 2011, and will be federally scheduled as a controlled substance due to incidences of euphoric mood seen in sedative-hypnotic abusers, similar to that of benzodiazpines.3 

GlaxoSmithKline is marketing Potiga™ as a novel neuronal potassium channel opener, specifically KCNQ2/3-type potassium channels, which decrease neuronal excitability under physiologic conditions.2,4 Ezogabine is also believed to potentiate GABA-evoked currents, block synthesis of neuroactive amino acids, and stimulate synthesis of GABA, although these are minor contributions to the anticonvulsant effect.4 It does not affect peripheral or cardiac voltage-gated potassium channels.2,4 

Ezogabine will be supplied in 50, 200, 300, and 400 mg immediate release tablets with a three times daily dosing frequency.3 It may be administered with or without food. Patients should be initiated on 100 mg of ezogabine three times daily.3 Dose increases of 50 mg/day should occur at weekly intervals with a maximum daily dose of 400 mg three times daily.3 For geriatric patients and those with Child-Pugh Class B hepatic impairment, the suggested initiation is 50 mg ezogabine three times daily, increased by 50 mg per week to a maximum daily dose of 250 mg three times daily.3 For individuals with a creatinine clearance <50 mL/min or Child-Pugh Class C hepatic impairment, the suggested initiation is 50 mg three times daily, increased by 50 mg per week to a maximum daily dose of 200 mg three times daily.3 

Potiga is hepatically metabolized by acetylation and glucuronidation, is excreted renally, and exhibits linear kinetics as well as a linear dose-response.4 Concomitant therapy with phenytoin and carbamazepine may yield a 30% decrease in ezogabine serum concentrations.4 Ezogabine dose adjustments may be considered when adding phenytoin or carbamazepine. Ezogabine can inhibit renal clearance of digoxin, thus increasing digoxin serum levels.4 

Treatment-emergent ADRs that lead to ezogabine discontinuation in clinical trials were primarily due to dizziness (6%), confusion (4%), fatigue (3%), and somnolence (3%)5, 6. Most common adverse effects are dose-related and similar to other AEDs including drowsiness, dizziness, fatigue, and somnolence.1,5,6 Ezogabine is associated with neuropsychiatric symptoms including confusion, hallucinations, and psychotic symptoms.1 These symptoms are more likely at high doses or during rapid dose titrations and can be minimized with a conservative dose titration. Ezogabine can cause cardiac conduction disturbances including QT-prolongation.1,3 The mean change in QT-interval was 7.7-msec from baseline in healthy volunteers.3 Ezogabine may cause urinary retention1, which is unique among anticonvulsants. When available, the FDA may require a patient-monitoring program to minimize complications from this effect. Symptoms of urinary retention include inability to initiate urination and painful or weak urination. Patients experiencing this should be referred for appropriate follow-up. Ezogabine is Pregnancy Category C due to inadequate data in pregnant women.3 Like other anticonvulsants, ezogabine will carry a warning for risk of suicidal thoughts or behaviors.1 

Ezogabine has been studied in individuals experiencing uncontrolled simple or complex partial seizures with and without secondary generalization who were prescribed one to three anticonvulsants with and without adjunctive vagus nerve stimulation.5–7 It has not been studied in primary generalized seizure disorders. The median percent-decreases in monthly seizures were 23% at 600 mg/day, 29% at 900 mg/day, and 35% at 1200 mg/day7. The calculated number needed to treat varies between 3 and 7 in efficacy studies for doses of 1200 mg ezogabine daily.5–7 

Because of ezogabine's unique mechanism of action as a neuronal potassium channels opener, it can rationally be used as adjunctive anticonvulsant therapy for refractory partial-onset seizures. Unfortunately, the three times daily dosing regimen may be suboptimal for treatment of a disease state where adherence is essential. With preliminary studies in animal and in vitro models, ezogabine may have some efficacy in the treatment of mania, migraine, neuropathic pain, and restless leg syndrome.4 Further studies are needed to evaluate ezogabine's role in these disease states.

1.
FDA Approves Potiga to Treat Seizures in Adults
.
FDA News Release. 2011. Available from: Please update this website to: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm258834.htm. Accessed June 13
.
2.
Weisenberg
JL
,
Wong
M.
Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures
.
Neuropsychiatr Dis Treat
.
2011
;
7
(
1
):
409
14
.
DOI: http://dx.doi.org/10.2147/NDT.S14208
.
3.
Rxlist.com. Potiga Drug Description
.
July 26, 2011
;
http://www.rxlist.com/potiga-drug.htm. Accessed November, 2011
.
4.
Stephen
LJ
,
Brodie
MJ.
Pharmacotherapy of epilepsy: newly approved and developmental agents
.
CNS Drugs
.
2011
;
25
(
2
):
89
107
. .
5.
French
JA
,
Abou-Khalil
BW
,
Leroy
RF
,
Yacubian
EMT
,
Shin
P
,
Hall
S
et al
.
Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy
.
Neurology
.
2011
;
76
(
18
):
1555
63
. .
6.
Brodie
MJ
,
Lerche
H
,
Gil-Nagel
A
,
Elger
C
,
Hall
S
,
Shin
P
et al
.
Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy
.
Neurology
.
2010
;
75
(
20
):
1817
24
. .
7.
Porter
RJ
,
Partiot
A
,
Sachdeo
R
,
Nohria
V
,
Alves
WM.
Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures
.
Neurology
.
2007
;
68
(
15
):
1197
204
. .

*This drug review was compiled prior to prescribing and package insert information being publicly available.