Retigabine

Overview

Retigabine (INN) or ezogabine (USAN) is an anticonvulsant used as an adjunctive treatment for partial epilepsies in treatment-experienced adult patients. The drug was developed by Valeant Pharmaceuticals and GlaxoSmithKline. It was approved by the European Medicines Agency under the trade name Trobalt on March 28, 2011, and by the United States Food and Drug Administration (FDA), under the trade name Potiga, on June 10, 2011. Production was discontinued in June 2017.[1][2][3] WP

Retigabine works primarily as a potassium channel opener—that is, by activating a certain family of voltage-gated potassium channels in the brain. This mechanism of action is unique among antiepileptic drugs, and may hold promise for the treatment of other neurologic conditions, including tinnitus, migraine and neuropathic pain. The manufacturer withdrew retigabine from clinical use in 2017 due to declining use, after the addition of a black box warning regarding side effects was added to the drug in 2013.[3–7] WP

Risks and side effects

Adverse effects

The adverse effects found in the Phase II trial mainly affected the central nervous system, and appeared to be dose-related. The most common adverse effects were drowsiness, dizziness, tinnitus and vertigo, confusion, and slurred speech. Less common side effects included tremor, memory loss, gait disturbances, and double vision.[8][9][10] WP

In 2013, FDA warned the public that the drug can cause blue skin discoloration and eye abnormalities, characterized by pigment changes in the retina. It was not known whether those changes were reversible at the time. The FDA added a black-box warning to the drug about these issues. Psychiatric symptoms and difficulty urinating were also reported, with most cases occurring in the first 2 months of treatment.[7][11][12][13] WP

The manufacturer stopped manufacturing retigabine in 2017 due to declining use.[7] WP

Interactions

Interactions

Retigabine appears to be free of drug interactions with most commonly used anticonvulsants. It may increase metabolism of lamotrigine (Lamictal), whereas phenytoin (Dilantin) and carbamazepine (CBZ, Tegretol) increase the clearance of retigabine.[13][14] WP

Concomitant use of retigabine and digoxin may increase serum concentration of the latter. In vitro studies suggest that the main metabolite of retigabine acts as a P-glycoprotein inhibitor, and may thus increase absorption and reduce elimination of digoxin.[13] WP

Pharmacology

Mechanism of action

Retigabine acts as a neuronal KCNQ/Kv7 potassium channel opener, a mechanism of action markedly different from that of any current anticonvulsants. This mechanism of action is similar to that of the chemically similar flupirtine, which is used mainly for its analgesic properties.[4][5][6][15] WP

The term "channel opener" refers to a shift in the voltage dependence for channel opening towards more negative potentials. This means that KCNQ/Kv7 channels open at more negative potentials in the presence of Retigabine. Recently, it has also been shown that Retigabine stabilizes the open Kv7.2/7.3 channel, making deactivation slower with little change in voltage dependence. This effect of Retigabine is observed at concentrations below 10 micromolar. A similar effect is observed on the homomeric Kv7.2 channel.[16][17] WP

Pharmacokinetics

Retigabine is quickly absorbed, and reaches maximum plasma concentrations between half an hour and 2 hours after a single oral dose. It has a moderately high oral bioavailability (50–60%), a high volume of distribution (6.2 L/kg), and a terminal half-life of 8 to 11 hours. Retigabine requires thrice-daily dosing due to its short half-life.[8][9][13][14] WP

Retigabine is metabolized in the liver, by N-glucuronidation and acetylation. The cytochrome P450 system is not involved. Retigabine and its metabolites are excreted almost completely (84%) by the kidneys.[13][14] WP

History

History

Among the newer anticonvulsants, retigabine was one of the most widely studied in the preclinical setting: it was the subject of over 100 published studies before clinical trials began. In preclinical tests, it was found to have a very broad spectrum of activity—being effective in nearly all the animal models of seizures and epilepsy used: retigabine suppresses seizures induced by electroshock, electrical kindling of the amygdala, pentylenetetrazol, kainate, NMDA, and picrotoxin. Researchers hoped this wide-ranging activity would translate to studies in humans as well.[8][18] WP

Clinical trials

In a double-blind, randomized, placebo-controlled Phase II clinical trial, retigabine was added to the treatment regimen of 399 participants with partial seizures that were refractory to therapy with other antiepileptic drugs. The frequency with which seizures occurred was significantly reduced (by 23 to 35%) in participants receiving retigabine, and approximately one fourth to one third of participants had their seizure frequency reduced by more than 50%. Higher doses were associated with a greater response to treatment.[8][9][10] WP

A Phase II trial meant to assess the safety and efficacy of retigabine for treating postherpetic neuralgia was completed in 2009, but failed to meet its primary endpoint. Preliminary results were reported by Valeant as "inconclusive".[19] WP

Regulatory approval

The U.S. Food and Drug Administration accepted Valeant's New Drug Application for retigabine on December 30, 2009. The FDA Peripheral and Central Nervous System Drugs Advisory Committee met on August 11, 2010, to discuss the process and unanimously recommended approval of Potiga for the intended indication (add-on treatment of partial seizures in adults). However, the possibility of urinary retention as an adverse effect was considered a significant concern, and the panel's members recommended that some sort of monitoring strategy be used to identify patients at risk of bladder dysfunction. Potiga was approved by the FDA on June 10, 2010, but did not become available on the U.S. market until it had been scheduled by the Drug Enforcement Administration.[12][20][21] WP

In December 2011, the U.S. Drug Enforcement Administration (DEA) placed the substance into Schedule V of the Controlled Substances Act (CSA), the category for substances with a comparatively low potential for abuse. This became effective 15 December 2011.[22] WP

Chemistry

Formula

C16H18FN3O2 PC

CAS number

150812-12-7 PC

Molar mass (g/mol)

303.33 PC

IUPAC name (computed by PubChem)

ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate PC

SMILES

CCOC(=O)NC1=C(C=C(C=C1)NCC2=CC=C(C=C2)F)N PC

InChIKey

PCOBBVZJEWWZFR-UHFFFAOYSA-N PC

PubChem CID

121892

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Other POTIGA (ezogabine) Tablets, CV. Full Prescribing Information
2. Other GlaxoSmithKline: Advance notification of trobalt discontinuation
3. Other Epilepsy drug Trobalt (retigabine) to be discontinued. 14 September 2016
4. Journal / agency Rundfeldt C. The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells. European Journal of Pharmacology. October 1997. doi:10.1016/S0014-2999(97)01249-1 · PMID 9384239
5. Journal / agency Main MJ, Cryan JE, Dupere JR, Cox B, Clare JJ, Burbidge SA. Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. Molecular Pharmacology. August 2000. doi:10.1124/mol.58.2.253 · PMID 10908292
6. Journal / agency Rogawski MA, Bazil CW. New molecular targets for antiepileptic drugs: alpha(2)delta, SV2A, and K(v)7/KCNQ/M potassium channels. Current Neurology and Neuroscience Reports. July 2008. doi:10.1007/s11910-008-0053-7 · PMID 18590620 · PMC2587091
7. Other MD, Veronica Hackethal. Anticonvulsant Potiga Discontinued in June 2017 | NeurologyLive - Clinical Neurology News and Neurology Expert Insights. 2025-12-19
8. Journal / agency Ben-Menachem E. Retigabine: has the orphan found a home?. Epilepsy Currents. 2007. doi:10.1111/j.1535-7511.2007.00209.x · PMID 18049722 · PMC2096728
9. Journal / agency Plosker GL, Scott LJ. Retigabine: in partial seizures. CNS Drugs. 2006. doi:10.2165/00023210-200620070-00005 · PMID 16800718
10. Journal / agency Porter RJ, Partiot A, Sachdeo R, Nohria V, Alves WM. Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures. Neurology. April 2007. doi:10.1212/01.wnl.0000259034.45049.00 · PMID 17420403
11. Journal / agency Potiga (Ezogabine): Drug Safety Communication
12. Other Hitt E. FDA approves ezogabine for seizures in adults. 2011-06-13
13. Other Trobalt – Summary of Product Characteristics (SPC). 2011-05-05
14. Journal / agency Luszczki JJ. Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions. Pharmacological Reports. 2009. doi:10.1016/s1734-1140(09)70024-6 · PMID 19443931
15. Journal / agency Brown DA, Passmore GM. Neural KCNQ (Kv7) channels. British Journal of Pharmacology. April 2009. doi:10.1111/j.1476-5381.2009.00111.x · PMID 19298256 · PMC2697739
16. Journal / agency Corbin-Leftwich A, Mossadeq SM, Ha J, Ruchala I, Le AH, Villalba-Galea CA. Retigabine holds KV7 channels open and stabilizes the resting potential. The Journal of General Physiology. March 2016. doi:10.1085/jgp.201511517 · PMID 26880756 · PMC4772374
17. Journal / agency Villalba-Galea CA. Modulation of KV7 Channel Deactivation by PI(4,5)P₂. Frontiers in Pharmacology. 2020-06-19. doi:10.3389/fphar.2020.00895 · PMID 32636742 · PMC7318307
18. Journal / agency Rogawski MA. Diverse mechanisms of antiepileptic drugs in the development pipeline. Epilepsy Research. June 2006. doi:10.1016/j.eplepsyres.2006.02.004 · PMID 16621450 · PMC1562526
19. Other Valeant Pharmaceuticals Announces Preliminary Results From Its Phase IIa Retigabine Study for the Treatment of Postherpetic Neuralgia (PHN). 2009-08-24
20. Other Retigabine NDA accepted for filing. 2009-12-30
21. Journal / agency [No authors listed]. August 11, 2010: Peripheral and Central Nervous System Drugs Advisory Committee Meeting Announcement. 2010-06-25
22. Journal / agency U.S. Drug Enforcement Administration. Schedules of Controlled Substances: Placement of Ezogabine Into Schedule V. Federal Register. 15 December 2011

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