Ezogabine (Retigabine) and Its Role in the Treatment of Partial-Onset Seizures: A Review

  • Michele Y. Splinter
    Address correspondence to: Michele Y. Splinter, PharmD, MS, 1100 North Stonewall Avenue, Oklahoma City, OK 73117
    Department of Pharmacy: Clinical and Administrative Sciences, University of Oklahoma Health Sciences Center, College of Pharmacy, Oklahoma City, Oklahoma
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      Ezogabine, also known as retigabine, is a recently approved anticonvulsant medication with a novel mechanism of action. It activates low-threshold voltage-gated potassium channels, leading to hyperpolarization of the membrane potential, stabilization of the resting membrane potential, and suppression of repetitive firing.


      This review identified the efficacy and tolerability of ezogabine in the treatment of partial-onset seizures reported in randomized controlled trials. Additional characteristics of the medication, including mechanism of action, pharmacokinetic properties, drug interactions, and additional applications under investigation are also addressed.


      MEDLINE and EMBASE were systematically searched, using the search terms retigabine and ezogabine, for randomized trials published from 1980 through February 8, 2012. Trials of the effects of adjunctive ezogabine in patients aged ≥16 years with partial seizures were included for analysis of clinical efficacy and tolerability. Articles that did not pertain to clinical efficacy and that did not report on randomized controlled trials were excluded. Articles relating to additional properties were reviewed for inclusion in the review.


      One Phase IIb and 2 Phase III trials were identified. Ezogabine has reported dose-dependent efficacy at doses of 600, 900, and 1200 mg/d. As with most anticonvulsant medications, the most common adverse events associated with ezogabine were central nervous system effects. Because potassium channels in the urothelium of the bladder are activated by ezogabine, a Risk Evaluation and Mitigation Strategy is in place regarding the risk for urinary retention and symptoms of acute urinary retention. There are limited drug interactions with ezogabine because it does not undergo metabolism by the cytochrome P450 system and is not highly protein bound.


      Ezogabine is a newly approved anticonvulsant for adjunctive therapy in partial-onset seizures in adults with a novel mechanism of action, activating low-threshold voltage-gated potassium channels. It has advantages over many of the available anticonvulsants in that it is not metabolized through the cytochrome P450 system and is not highly protein bound, therefore limiting its potential for drug–drug interactions. Unique to ezogabine compared with other anticonvulsants is its association with urinary retention due to its effect on potassium channels in the urothelium of the bladder.

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        • Ngugi A.K.
        • Kariuki S.M.
        • Bottomley C.
        • et al.
        Incidence of epilepsy: a systematic review and meta-analysis.
        Neurology. 2011; 77: 1005-1012
        • Brodie M.J.
        • Kwan P.
        Staged approach to epilepsy management.
        Neurology. 2002; 8: S2-S8
        • Callaghan B.C.
        • Anand K.
        • Hesdorffer D.
        • et al.
        Likelihood of seizure remission in an adult population with refractory epilepsy.
        Ann Neurol. 2007; 62: 382-389
        • Luciano A.L.
        • Shorvon S.D.
        Results of treatment changes in patients with apparently drug-resistant chronic epilepsy.
        Ann Neurol. 2007; 62: 375-381
      1. Potiga (ezagabine) tablets [product information].
        (Accessed February 8, 2012)
        • Rundfeldt C.
        • Netzer R.
        The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits.
        Neurosci Lett. 2000; 282: 73-76
        • Dencker D.
        • Husum H.
        Antimanic efficacy of retigabine in a proposed mouse model of bipolar disorder.
        Behav Brain Res. 2010; 207: 78-83
        • Hempel R.
        • Schupke H.
        • McNeilly P.J.
        • et al.
        Metabolism of retigabine (D-23129), a novel anticonvulsant.
        Drug Metab Dispos. 1999; 27: 613-622
        • Lange W.
        • Geissendorfer J.
        • Schenzer A.
        • et al.
        Refinement of the binding site and mode of action of the anticonvulsant retigabine on KCNQ K+ channels.
        Mol Pharmacol. 2009; 75: 272-280
        • Cooper E.C.
        • Jan L.Y.
        M-channels: Neurological diseases, neuromodulation, and drug development.
        Arch Neurol. 2003; 60: 496-500
        • Brown D.A.
        • Passmore G.M.
        Neural KCNQ (Kv7) channels.
        Br J Pharmacol. 2009; 156: 1185-1195
        • Wickenden A.D.
        • McNaughton-Smith G.
        Kv7 channels as targets for the treatment of pain.
        Curr Pharm Des. 2009; 15: 1773-1798
        • Dost R.
        • Rostock A.
        • Rundfeldt C.
        The anti-hyperalgesic activity of retigabine is mediated by KCNQ potassium channel activation.
        Naunyn-Schmiedeberg's Arch Pharmacol. 2004; 369: 382-390
        • Gao Z.
        • Zhang T.
        • Wu M.
        • et al.
        Isoform-specific prolongation of Kv7 (KCNQ) potassium channel opening mediated by new molecular determinants for drug-channel interactions.
        J Biol Chem. 2010; 285: 28322-28332
        • Otto J.F.
        • Kimball M.M.
        • Wilcox K.S.
        Effects of the anticonvulsant retigabine on cultured cortical neurons: changes in electroresponsive properties and synaptic transmission.
        Mol Pharmacol. 2002; 61: 921-927
        • Sills G.J.
        • Rundfeldt C.
        • Butler E.
        • et al.
        A neurochemical study of the novel antiepileptic drug retigabine in mouse brain.
        Pharmacol Res. 2000; 42: 553-557
        • Kapetanovic I.M.
        • Yonekawa W.D.
        • Kupferberg H.J.
        The effects of D-23129, a new experimental anticonvulsant drug, on neurotransmitter amino acids in the rat hippocampus in vitro.
        Epilepsy Res. 1995; 22: 167-173
        • Tober C.
        • Rostock A.
        • Rundfeldt C.
        • Bartsch R.
        D-23129: A potent anticonvulsant in the amygdala kindling model of complex partial seizures.
        Eur J Pharmacol. 1996; 303: 163-169
        • Dailey J.W.
        • Cheong J.H.
        • Ko K.H.
        • et al.
        Anticonvulsant properties of D-20443 in genetically epilepsy-prone rats: prediction of clinical response.
        Neurosci Lett. 1995; 195: 77-80
        • Xu W.
        • Wu Y.
        • Bi Y.
        • et al.
        Activation of voltage-gated KCNQ/Kv7 channels by anticonvulsant retigabine attenuates mechanical allodynia of inflammatory temporomandibular joint in rats.
        Mol Pain. 2010; 6: 49
        • Nodera H.
        • Spieker A.
        • Sung M.
        • Rutkove S.
        Neuroprotective effects of Kv7 channel agonist, retigabine, for cisplatin-induced peripheral neuropathy.
        Neurosci Lett. 2011; 505: 223-227
        • Ferron G.M.
        • Paul J.
        • Fruncillo R.
        • et al.
        Multiple-dose, linear, dose-proportional pharmacokinetics of retigabine in healthy volunteers.
        J Clin Pharmacol. 2002; 42: 175-182
        • Borlak J.
        • Gasparic A.
        • Locher M.
        • et al.
        N-Glucuronidation of the antiepileptic drug retigabine: results from studies with human volunteers, heterologously expressed human UGTs, human liver, kidney, and liver microsomal membranes of Crigler-Najjar type II.
        Metabolism. 2006; 55: 711-721
        • Hiller A.
        • Nguyen N.
        • Strassburg C.P.
        • et al.
        Retigabine N-glucuronidation and its potential role in enterohepatic circulation.
        Drug Metab Dispos. 1999; 27: 605-612
        • Shin P.
        • Loewen G.
        • Mansbach H.
        • et al.
        Effect of renal impairment on retigabine pharmacokinetics.
        Epilepsia. 2008; 49 (Abstract 1.265): 116
        • Mansbach H.
        • Loewen G.
        • Shin P.
        • et al.
        Effect of hepatic impairment on retigabine pharmacokintics.
        Epilepsia. 2008; 49 (Abstract 1.260): 114
        • Hermann R.
        • Ferron G.M.
        • Erb K.
        • et al.
        Effects of age and sex on the disposition of retigabine.
        Clin Pharmacol Ther. 2003; 73: 61-70
        • Tompson D.J.
        • Vanlandingham K.E.
        The effects of retigabine on the pharmacokinetics of concomitantly administered antiepileptic drugs.
        Epilepsia. 2010; 51: 123-124
        • Hermann R.
        • Knebel N.G.
        • Niebch G.
        • et al.
        Pharmacokinetic interaction between retigabine and lamotrigine in healthy subjects.
        Eur J Clin Pharmacol. 2003; 58: 795-802
        • Paul J.
        • Ferron G.M.
        • Richards L.
        • et al.
        Retigabine does not alter the pharmacokinetics of a low-dose oral contraceptive in women.
        Neurology. 2001; 56: A335-A336
        • Hansen H.
        • Loewen G.
        • Shin P.
        • Mansbach H.
        Lack of significant pahrmacokinetic interaction between retigabine and oral contraceptive hormones.
        Epilepsia. 2008; 49: 113
        • Clinical Trials
        An open-label, single-centre study evaluating the pharmacokinetics of digoxin alone and when administered at various doses of ezogabine/retigabine in healthy adults.
        (Accessed June 18, 2012)
        • Ferron G.M.
        • Sachdeo R.
        • Partiot A.
        • et al.
        Pharmacokinetic interaction between valproic acid, topiramate, phenytoin or carbamazepine and retigabine in epileptic patients.
        Clin Pharmacol Ther. 2001; 69: P18
        • Ferron G.M.
        • Patat A.
        • Parks V.
        • et al.
        Lack of pharmacokinetic interaction between retigabine and phenobarbitone at steady-state in healthy subjects.
        Br J Clin Pharmacol. 2003; 56: 39-45
        • Porter R.J.
        • Partiot A.
        • Sachdeo R.
        • et al.
        Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures.
        Neurology. 2007; 68: 1197-1204
        • Brodie M.J.
        • Lerche H.
        • Gil-Nagel A.
        • et al.
        Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy.
        Neurology. 2010; 75: 1817-1824
        • French J.A.
        • Abou-Khalil B.W.
        • Leroy R.F.
        • et al.
        Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy.
        Neurology. 2011; 76: 1555-1563
        • Lerche H.
        • Leroy R.
        • Hall S.
        • et al.
        Long-term maintenance of efficacy with retigabine 600-1200 mg/day in adult patients with refractory epilepsy: Extension study of RESTORE 2.
        Epilepsia. 2010; 51 (Abstract): 77-78
        • Leroy R.
        • Rosenfeld W.
        • Hall S.
        • et al.
        Long-term maintenance of efficacy with retigabine 600-1200 mg/day in adult patients with refractory epilepsy: extension study of RESTORE 1.
        Epilepsia. 2010; 51 (Abstract): 77
        • Elger C.E.
        • Brodie M.J.
        • Lee W.-J.
        • et al.
        Long-term maintenance of efficacy and tolerability with retigabine (ezogabine) 600-1200 mg/day over 24 months.
        Epilepsia. 2011; 52: 114
        • DeRossett S.E.
        • Brickel N.
        • Hall S.T.
        Pharmacological effects of retigabine (ezogabine) on bladder function].
        Epilepsia. 2011; 52: 114-115
      2. Potiga Risk Evaluation and Mitigation Strategy (REMS).
        (Accessed February 8, 2012)
        • Mohanraj R.
        • Norrie J.
        • Stephen L.J.
        • et al.
        Mortality in adults with newly diagnosed and chronic epilepsy: a retrospective comparative study.
        Lancet Neurol. 2006; 5: 481-487
        • Brickel N.
        • Hall S.T.
        • DeRossett S.E.
        Cardiac safety and rates of sudden unexplained death in patients with epilepsy treated with retigabine (ezogabine).
        Epilepsia. 2011; 52: 250-251
        • Ryvlin P.
        • Cucherat M.
        • Rheims S.
        Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: A meta-analysis of placebo-controlled randomised trials.
        Lancet Neurol. 2011; 10: 961-968
      3. Clinical Trials.
        (Accessed August 10, 2012)
      4. Clinical Trials.
        (Accessed August 10, 2012)
      5. Clinical Trials.
        (Accessed August 4, 2012)
        • Rode F.
        • Svalo J.
        • Sheykhzade M.
        • Ronn L.C.B.
        Functional effects of the KCNQ modulators retigabine and XE991 in the rat urinary bladder.
        Eur J Pharmacol. 2010; 638: 121-127
        • Splinter M.Y.
        Pharmacokinetics of new antiepileptic medications.
        J Pharmacy Pract. 2005; 18: 444-460