Clinical summary of the Retigabin 2025-09-26 07:53:12

Clinical summary of the Retigabin

Clinical Summary of Retigabine

Retigabine (international nonproprietary name; known as ezogabine in the United States) represents a significant development in antiepileptic pharmacotherapy, being the first-in-class potassium channel opener for the adjunctive treatment of partial-onset seizures (POS) in adults. Below is a comprehensive clinical summary, including its pharmacological profile, efficacy, safety, pharmacokinetics, regulatory history, and eventual withdrawal from the market, based on the provided sources.

1. Pharmacological Profile

1.1 Mechanism of Action

Retigabine’s primary mechanism distinguishes it from other antiepileptic drugs (AEDs): it acts as a positive allosteric modulator of neuronal KCNQ (Kv7.2–7.5) potassium channels, especially the heteromeric KCNQ2/3 channels (Gunthorpe et al., 2012); (Weisenberg & Wong, 2011). These channels are critical for stabilizing the neuronal membrane potential and controlling cellular excitability. Mutations in KCNQ2/3 channels are associated with benign familial neonatal convulsions, providing a direct molecular rationale for targeting these channels in epilepsy (Gunthorpe et al., 2012).

Retigabine binds to a hydrophobic pocket near the channel gate, shifting the voltage dependence for channel opening toward more negative potentials and stabilizing the open state of the channel. This hyperpolarizes the neuronal membrane, reducing excitability and the likelihood of seizure propagation (Gunthorpe et al., 2012).

1.2 Pharmacokinetics

Absorption: Rapid, with peak plasma concentrations within 0.5–2 hours post-oral dosing.
Bioavailability: Approximately 50–60%.
Distribution: High volume of distribution (~6.2 L/kg).
Metabolism: Primarily hepatic via N-glucuronidation and acetylation; cytochrome P450 enzymes are not significantly involved (Weisenberg & Wong, 2011).
Elimination: Renal excretion of drug and metabolites (~84%).
Half-life: Mean ~8 hours (range 7–11 hours), necessitating three times daily dosing (Weisenberg & Wong, 2011).

2. Clinical Efficacy

2.1 Indications

Retigabine was approved as adjunctive therapy for adults with partial-onset seizures refractory to other AEDs (Weisenberg & Wong, 2011); (Wikipedia, n.d.).

2.2 Clinical Trials

Efficacy was demonstrated in three pivotal randomized, double-blind, placebo-controlled trials:

Porter et al. (2007): Ezogabine at 600, 900, and 1200 mg/day produced median seizure frequency reductions of 23.4%, 29.3%, and 35.2%, respectively, versus 13.1% for placebo. The proportion of patients achieving >50% reduction in seizure frequency was 23.2%, 31.6%, and 33.0% for the respective doses vs. 15.6% for placebo (Weisenberg & Wong, 2011).
RESTORE 2 (Brodie et al., 2010): At 600 and 900 mg/day, seizure frequency was reduced by 27.9% and 39.9%. >50% reduction in seizures was seen in 38.6% and 47.0% of patients, compared to 18.9% for placebo.
RESTORE 1 (French et al., 2011): 1200 mg/day showed a median seizure frequency reduction of 35.2% and >50% seizure reduction in 33.0% of patients versus 15.6% for placebo.

These results indicate a clear dose-dependent efficacy, with approximately one-third of patients achieving a clinically meaningful (>50%) reduction in seizure frequency (Weisenberg & Wong, 2011).

3. Safety and Adverse Effects

3.1 Common Adverse Events

The most frequently observed side effects were central nervous system (CNS) related and dose-dependent:

Dizziness: Up to 40.5% in some trials
Somnolence: Up to 31.4%
Fatigue, confusion, dysarthria, ataxia, blurred vision, tremor, nausea, headache, vertigo, amnesia, and speech disorder were also frequent (Weisenberg & Wong, 2011).

3.2 Urinary Effects

Retigabine’s mechanism also affects bladder smooth muscle, leading to:

Urinary retention-related adverse events: More frequent with retigabine than placebo (e.g., urinary hesitation, increased post-void residuals, dysuria, chromaturia)
Urinary tract infections: 11.8% in the ezogabine group vs 8.6% for placebo (Brickel et al., 2012); (Weisenberg & Wong, 2011).

Urinary retention was most frequently reported within the first two months of treatment and generally resolved upon discontinuation.

3.3 Pigmentation Disorders

After market approval, serious concerns emerged regarding tissue discoloration:

Blue/grey discoloration: Affected the skin, lips, nails, and ocular tissues (including retina).
Ophthalmological events: Retinal pigmentation and rare acquired vitelliform maculopathy identified on eye examination.
- In long-term extension studies, abnormal retinal pigmentation was observed in up to 32% of patients undergoing eye exams.
- Dermatological discoloration was reported in up to 62% in some cohorts.
- Complete resolution after discontinuation was infrequent; in some follow-ups, only 2/3 (skin), 0/0 (lips), 7/13 (nails), and 1/11 (mucosa) showed full resolution (Brickel et al., 2020).

3.4 Other Adverse Events

Psychiatric symptoms and memory disturbances were reported, though less frequent.
No significant hepatic, cardiac, or hematologic toxicity was identified in clinical trials (Weisenberg & Wong, 2011).

4. Drug Interactions

Retigabine exhibits minimal interaction with most AEDs, with some exceptions:

Increased metabolism of lamotrigine when co-administered
Increased clearance of retigabine when combined with phenytoin or carbamazepine
Potential for increased digoxin levels due to P-glycoprotein inhibition by metabolites (Wikipedia, n.d.); (Weisenberg & Wong, 2011).

5. Regulatory History and Market Withdrawal

Approval: EMA (March 28, 2011 as Trobalt), FDA (June 10, 2011 as Potiga) for adjunctive therapy in adult POS (Wikipedia, n.d.).
DEA Scheduling: Placed in Schedule V (lowest abuse potential) in December 2011.
Restriction and Withdrawal:
- 2013: Indication restricted due to pigmentation side effects.
- 2017: Voluntarily withdrawn due to limited clinical use, driven by safety concerns and market factors (Wikipedia, n.d.); (Brickel et al., 2020).

6. Conclusion

Retigabine was a mechanistically novel AED with proven efficacy as adjunctive therapy for refractory partial-onset seizures in adults, offering a much-needed alternative for patients unresponsive to other treatments. Its unique mechanism of action—opening neuronal KCNQ potassium channels—provided a fresh therapeutic avenue.

However, its clinical utility was ultimately overshadowed by serious safety concerns, particularly irreversible tissue pigmentation and urinary retention, which led to significant regulatory action and its withdrawal from the market. Despite these drawbacks, retigabine’s development has expanded understanding of potassium channel pharmacology and its potential in neurological diseases.

References

REFERENCES

The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy - PubMed - last accessed: 2025-09-26

Retigabine - Wikipedia - last accessed: 2025-09-26

The urinary safety profile and secondary renal effects of retigabine (ezogabine): a first-in-class antiepileptic drug that targets KCNQ (K(v)7) potassium channels - PubMed - last accessed: 2025-09-26

Safety of retigabine in adults with partial-onset seizures after long-term exposure: focus on unexpected ophthalmological and dermatological events - PubMed - last accessed: 2025-09-26

Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures - PMC - last accessed: 2025-09-26

Sources used

QUERY: Retigabine AND clinical trial AND efficacy

Efficacy and tolerability exposure-response relationship of retigabine (ezogabine) immediate-release tablets in patients with partial-onset seizures.
Clinical therapeutics. 2012/5/30; Impact Factor: 2.72, Quartile: Q1
DOI: 10.1016/j.clinthera.2013.06.012
PMID: 23916044
Abstract
Retigabine (international nonproprietary name)/ezogabine (United States adopted name) is an antiepileptic drug (AED) that enhances KCNQ (Kv7) potassium channel activity.
The aim of this study was to explore the relationship between retigabine/ezogabine systemic exposure and efficacy and adverse events (AEs) of retigabine/ezogabine from Phase III clinical trials.
Data were combined from Studies 301 and 302, which were both randomized, double-blind, placebo-controlled, multicenter, parallel-group studies with similar inclusion and exclusion criteria. All patients had partial-onset seizures and were receiving 1 to 3 concomitant AEDs. Systemic exposure was predicted for each patient as the average steady-state AUC0-τ during the 12-week maintenance phase, based on a population pharmacokinetic model developed for retigabine/ezogabine. Efficacy end points included reduction in total partial-seizure frequency from baseline and probability of ≥50% reduction from baseline in seizure frequency. The probabilities of occurrence of 6 AEs were also evaluated.
AUC0-τ values increased linearly over the 600- to 1200-mg/d dose range. Over the entire AUC0-τ range, the probability of efficacy was greater than that for any AE. The slopes of the exposure-response relationship for probability of dizziness and abnormal coordination were similar to that for efficacy, whereas the slopes for dysarthria, somnolence, tremor, and blurred vision were shallower, indicating that the probability of these events occurring was less affected than the probability of efficacy by increases in retigabine/ezogabine AUC0-τ.
Based on the summary statistics of pharmacokinetic parameters, systemic exposure to retigabine/ezogabine increased linearly with dose (600-1200 mg/d). Population pharmacokinetics and pharmacodynamics showed that the probability of efficacy and AEs increased with increasing systemic retigabine/ezogabine exposure, and the probability of efficacy was higher than the probability of any of the AEs. The 35%-50% between-patient variability and overlap between retigabine/ezogabine dose levels in AUC0-τ values indicate that, as with other AEDs, doses should be individually titrated based on a balance between efficacy and tolerability.

QUERY: Retigabine AND safety AND adverse effects

Update on Antiepileptic Drugs 2019.
Continuum (Minneapolis, Minn.). 2019/3/29; Impact Factor: 2.52, Quartile: Q1
DOI: 10.1212/CON.0000000000000715
PMID: 30921021
Abstract
This article is an update from the article on antiepileptic drug (AED) therapy published in the last Continuum issue on epilepsy and is intended to cover the vast majority of agents currently available to the neurologist in the management of patients with epilepsy. Treatment of epilepsy starts with AED monotherapy. Knowledge of the spectrum of efficacy, clinical pharmacology, and modes of use for individual AEDs is essential for optimal treatment for epilepsy. This article addresses AEDs individually, focusing on key pharmacokinetic characteristics, indications, and modes of use.
Since the previous version of this article was published, three new AEDs, brivaracetam, cannabidiol, and stiripentol, have been approved by the US Food and Drug Administration (FDA), and ezogabine was removed from the market because of decreased use as a result of bluish skin pigmentation and concern over potential retinal toxicity.Older AEDs are effective but have tolerability and pharmacokinetic disadvantages. Several newer AEDs have undergone comparative trials demonstrating efficacy equal to and tolerability at least equal to or better than older AEDs as first-line therapy. The list includes lamotrigine, oxcarbazepine, levetiracetam, topiramate, zonisamide, and lacosamide. Pregabalin was found to be less effective than lamotrigine. Lacosamide, pregabalin, and eslicarbazepine have undergone successful trials of conversion to monotherapy. Other newer AEDs with a variety of mechanisms of action are suitable for adjunctive therapy. Most recently, the FDA adopted a policy that a drug's efficacy as adjunctive therapy in adults can be extrapolated to efficacy in monotherapy. In addition, efficacy in adults can be extrapolated for efficacy in children 4 years of age and older. Both extrapolations require data demonstrating that an AED has equivalent pharmacokinetics between its original approved use and its extrapolated use. In addition, the safety of the drug in pediatric patients has to be demonstrated in clinical studies that can be open label. Rational AED combinations should avoid AEDs with unfavorable pharmacokinetic interactions or pharmacodynamic interactions related to mechanism of action.
Knowledge of AED pharmacokinetics, efficacy, and tolerability profiles facilitates the choice of appropriate AED therapy for patients with epilepsy.

QUERY: Retigabine AND pharmacology AND epilepsy

Web Sources

Safety of retigabine in adults with partial-onset seizures after long-term exposure: focus on unexpected ophthalmological and dermatological events - PubMed

@gsk.com. 5 GSK, Warsaw, Poland. Electronic address: jerzy.2.daniluk@gsk.com. 6 GSK, Mumbai, India. Electronic address: kalpesh.k.joshi@gsk.com. 7 Instituto Nacional de Neurologia y Neurocirugia "Manuel Velasco Suarez", Tlalpan, Mexico. 8 Division of Neurology, Department of Medicine, Faculty of Medicine, Integrated Epilepsy Research Group, Khon Kaen University, Thailand. 9 Central Clinical Hospital #2 OAO RZD, Rehabilitation Department, Moscow, Russia; IM Sechenov First Moscow State Medical University (Sechenovskiy University), Ministry of Health, Russia. 10 GSK, Brentford, Middlesex, UK. Electronic address: james.5.cooper@gsk.com. PMID: 31731109 DOI: 10.1016/j.yebeh.2019.106580 Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID Abstract Background: Retigabine is an antiepileptic drug developed for the adjunctive treatment of adults with epilepsy and partial-onset seizures (POS). Following its approval in 2011, reports of ophthalmological/dermatological pigmentation/discoloration led to a restriction of the indication in 2013, and in 2017, retigabine was voluntarily withdrawn from the market because of its limited usage. Here, data are reported from four open-label extension studies focusing on long-term safety with particular emphasis on ophthalmological and dermatological events. Methods: Studies 113413 ( NCT01336621 ), 114873 ( NCT01777139 ), 115097 ( NCT00310388 ), and 115098 ( NCT00310375 ) were multicenter, open-label extension studies of retigabine (300-1200 mg/day) for the adjunctive treatment of adults with POS. Safety assessments included monitoring treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). When new safety issues were identified, protocols were amended to include additional on-treatment safety evaluations, including ophthalmological and dermatological examinations. Patients who had abnormal retinal pigmentation, unexplained vision change, pigmentation of nonretinal ocular tissue, or abnormal discoloration of skin

Retigabine - Wikipedia

oxin . [ 18 ] Researchers hoped this wide-ranging activity would translate to studies in humans as well. [ 8 ] Clinical trials [ edit ] 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 ] [ 10 ] [ 9 ] 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 ] Regulatory approval [ edit ] The U.S. Food and Drug Administration accepted Valeant's New Drug Application for retigabine on December 30, 2009. [ 20 ] 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). [ 21 ] [ 22 ] 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. [ 21 ] 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 ] 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. [ 23 ] Name [ edit ] The International Nonproprietary Name "retigabine" was initially published as being under consideration by WHO in 1996. [ 24 ] This was later adopted as the recommended International Nonproprietary Name (rINN) for the drug, and, in 2005 or 2006, the USAN Council —a program sponsored by the American Medical Association, the United States Pharmacopeial Convention

Retigabine - Wikipedia

Safety of retigabine in adults with partial-onset seizures after long-term exposure: focus on unexpected ophthalmological and dermatological events - PubMed

, nails, and/or mucosa resolved completely in 2/3, 0/0, 7/13, and 1/11 patients, respectively. Conclusions: The safety profile of retigabine in adults with POS across four open-label studies was generally consistent with data from previous placebo-controlled studies. Discoloration of various tissues occurred in a proportion of patients treated with retigabine and resolved completely in a small number of these patients following treatment discontinuation. In addition, comprehensive eye examination identified a new adverse reaction of acquired vitelliform maculopathy in a limited number of patients. Keywords: Acquired vitelliform maculopathy; Epilepsy; Long-term safety; Retigabine; Retinal pigmentation; Skin discoloration. Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved. PubMed Disclaimer Publication types Multicenter Study Actions Search in PubMed Search in MeSH Add to Search Randomized Controlled Trial Actions Search in PubMed Search in MeSH Add to Search Research Support, Non-U.S. Gov't Actions Search in PubMed Search in MeSH Add to Search MeSH terms Adult Actions Search in PubMed Search in MeSH Add to Search Anticonvulsants / administration & dosage Actions Search in PubMed Search in MeSH Add to Search Anticonvulsants / adverse effects Actions Search in PubMed Search in MeSH Add to Search Carbamates / administration & dosage Actions Search in PubMed Search in MeSH Add to Search Carbamates / adverse effects Actions Search in PubMed Search in MeSH Add to Search Double-Blind Method Actions Search in PubMed Search in MeSH Add to Search Drug Administration Schedule Actions Search in PubMed Search in MeSH Add to Search Drug Therapy, Combination Actions Search in PubMed Search in MeSH Add to Search Eye Diseases / chemically induced Actions Search in PubMed Search in MeSH Add to Search Eye Diseases / diagnosis Actions Search in PubMed Search in MeSH Add to Search Female Actions Search in PubMed Search in MeSH Add to Search Follow-Up Studies Actions Search in PubMed Search in MeSH Add to Search Humans Actions Search in PubMed Search in MeSH Add to Search Male Actions Search in PubMed Search in MeSH Add to Search Middle Aged Actions Search in PubMed Search in MeSH Add to Search Phenylenediamines / administration & dosage Actions Search in PubMed Search in MeSH Add to Search Phenylenediamines / adverse effects Actions Search in

Retigabine - Wikipedia

Retigabine - Wikipedia Jump to content Main menu Main menu move to sidebar hide Navigation Main page Contents Current events Random article About Wikipedia Contact us Contribute Help Learn to edit Community portal Recent changes Upload file Special pages Search Search Appearance Donate Create account Log in Personal tools Donate Create account Log in Pages for logged out editors learn more Contributions Talk Contents move to sidebar hide (Top) 1 Adverse effects 2 Interactions 3 Pharmacology Toggle Pharmacology subsection 3.1 Mechanism of action 3.2 Pharmacokinetics 4 History Toggle History subsection 4.1 Clinical trials 4.2 Regulatory approval 5 Name 6 References 7 Further reading Toggle the table of contents Retigabine 11 languages العربية Deutsch Español فارسی Français Polski Română Српски / srpski Srpskohrvatski / српскохрватски Tiếng Việt 中文 Edit links Article Talk English Read Edit View history Tools Tools move to sidebar hide Actions Read Edit View history General What links here Related changes Upload file Permanent link Page information Cite this page Get shortened URL Download QR code Print/export Download as PDF Printable version In other projects Wikimedia Commons Wikidata item Appearance move to sidebar hide From Wikipedia, the free encyclopedia Anticonvulsant, which works as a potassium-channel opener Pharmaceutical compound Retigabine Clinical data Trade names Trobalt, Potiga Other names D-23129, ezogabine ( USAN US ) AHFS / Drugs.com Professional Drug Facts MedlinePlus a612028 License data EU EMA : by INN US FDA : Ezogabine Routes of administration By mouth ATC code N03AX21 ( WHO ) Legal status Legal status AU : S4 (Prescription only) UK : POM (Prescription only) US : Schedule V Pharmacokinetic data Bioavailability 60% Protein binding 60–80% Metabolism Liver glucuronidation and acetylation . CYP not involved Elimination half-life 8 hours (mean), range: 7–11 hours [ 1 ] Excretion Kidney (84%) Identifiers IUPAC name Ethyl N -[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate

Retigabine - Wikipedia

Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures - PMC

/WNL.0b013e3181fd6170. [ DOI ] [ PubMed ] [ Google Scholar ] 25. French JA, Abou-Khalil BW, Leroy RF, et al. Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy. Neurology. 2011;76:1555–1563. doi: 10.1212/WNL.0b013e3182194bd3. [ DOI ] [ PubMed ] [ Google Scholar ] 26. Streng T, Christoph T, Andersson KE. Urodynamic effects of the K+ channel (KCNQ) opener retigabine in freely moving, conscious rats. J Urol. 2004;172:2054–2058. doi: 10.1097/01.ju.0000138155.33749.f4. [ DOI ] [ PubMed ] [ Google Scholar ] 27. Rode F, Svalo J, Sheykhzade M, Ronn LCB. Functional effects of the KCNQ modulators retigabine and XE991 in the rat urinary bladder. Eur J Pharmacol. 2010;638:121–127. doi: 10.1016/j.ejphar.2010.03.050. [ DOI ] [ PubMed ] [ Google Scholar ] 28. McNeilly RJ, Torchin CD, Anderson LW, Kapetanovic IM, Kupferberg HJ, Strong JM. In vitro glucuronidation of D-23129, a novel anticonvulsant, by human liver microsomes and liver slices. Xenobiotica. 1997;27:431–441. doi: 10.1080/004982597240424. [ DOI ] [ PubMed ] [ Google Scholar ] 29. Hempel R, Schupke H, McNeilly PJ, et al. Metabolism of retigabine (D-23129), a novel anticonvulsant. Drug Metab Dispos. 1999;27:613–622. [ PubMed ] [ Google Scholar ] 30. Hiller A, Nguyen N, Strassburg C, et al. Retigabine N-glucuronidation and its potential role in enterohepatic circulation. Drug Metab Dispos. 1999;27:

The urinary safety profile and secondary renal effects of retigabine (ezogabine): a first-in-class antiepileptic drug that targets KCNQ (K(v)7) potassium channels - PubMed

: ( change ) Frequency: Monthly Weekly Daily Which day? The first Sunday The first Monday The first Tuesday The first Wednesday The first Thursday The first Friday The first Saturday The first day The first weekday Which day? Sunday Monday Tuesday Wednesday Thursday Friday Saturday Report format: Summary Summary (text) Abstract Abstract (text) PubMed Send at most: 1 item 5 items 10 items 20 items 50 items 100 items 200 items Send even when there aren't any new results Optional text in email: Save Cancel Create a file for external citation management software Create file Cancel Your RSS Feed Name of RSS Feed: Number of items displayed: 5 10 15 20 50 100 Create RSS Cancel RSS Link Copy Full text links Wiley Full text links Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Permalink Permalink Copy Display options Display options Format Abstract PubMed PMID Page navigation Title & authors Abstract Publication types MeSH terms Substances LinkOut - more resources Title & authors Abstract Publication types MeSH terms Substances LinkOut - more resources Review Epilepsia Actions Search in PubMed Search in NLM Catalog Add to Search . 2012 Apr;53(4):606-12. doi: 10.1111/j.1528-1167.2012.03441.x. Epub 2012 Mar 16. The urinary safety profile and secondary renal effects of retigabine (ezogabine): a first-in-class antiepileptic drug that targets KCNQ (K(v)7) potassium channels Neil Brickel 1 , Paul Gandhi , Kevan VanLandingham , Janet Hammond , Sarah DeRossett Affiliations Expand Affiliation 1 GlaxoSmithKline, Stockley Park, Middlesex, UK. neil.r.brickel@gsk.com PMID: 22428574 DOI: 10.1111/j.1528-1167.2012.03441.x Item in Clipboard Review The urinary safety profile and secondary renal effects of retigabine (ezogabine): a first-in-class antiepileptic drug that targets KCNQ (K(v)7) potassium channels Neil Brickel et al. Epilepsia . 2012 Apr . Show details Display options Display options Format Abstract PubMed PMID Epilepsia Actions Search

Safety of retigabine in adults with partial-onset seizures after long-term exposure: focus on unexpected ophthalmological and dermatological events - PubMed

amended to include additional on-treatment safety evaluations, including ophthalmological and dermatological examinations. Patients who had abnormal retinal pigmentation, unexplained vision change, pigmentation of nonretinal ocular tissue, or abnormal discoloration of skin, lips, nails, and/or mucosa at the end of the treatment phase were asked to enter a safety follow-up continuation phase comprising 6-monthly ophthalmological/dermatological assessments. Results: The safety population (patients receiving ≥1 dose of retigabine in the open-label phase) comprised 98, 30, 376, and 181 patients for studies 113413, 114873, 115097, and 115098, respectively. Mean (standard deviation) treatment exposure ranged from 529 (424) to 1129 (999) days. In total, 68%-96% and 4%-27% of patients across the studies experienced TEAEs and TE SAEs, respectively. There were seven on-treatment deaths and two after discontinuation. Overall, 14%-73% of patients had an on-treatment eye examination, of whom 8/53, 4/22, 17/54, and 14/36 had abnormal retinal pigmentation and 15/53, 7/22, 15/54, and 11/36 had nonretinal ocular pigmentation in studies 113413, 114873, 115097, and 115098, respectively. Four patients had confirmed acquired vitelliform maculopathy. In patients with unresolved events at discontinuation and ≥1 posttreatment follow-up, retinal pigmentation resolved completely in 1/3, 0/3, 0/10, and 1/7 patients and nonretinal ocular pigmentation in 1/4, 0/3, 8/10, and 4/6 patients, respectively. Overall, 12%-83% of patients had an on-treatment dermatological examination, of whom 11/58, 0/25, 23/46, and 23/37 had any-tissue discoloration, respectively. In patients with unresolved events at discontinuation and ≥1 posttreatment follow-up, discoloration of skin, lips, nails, and/or mucosa resolved completely in 2/3, 0/0, 7/13, and 1/11 patients, respectively. Conclusions: The safety profile of retigabine in adults with POS across four open-

The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy - PubMed

The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Retigabine - Wikipedia

07-19 . Further reading [ edit ] Blackburn-Munro G, Dalby-Brown W, Mirza NR, Mikkelsen JD, Blackburn-Munro RE (2005). "Retigabine: chemical synthesis to clinical application" . CNS Drug Reviews . 11 (1): 1– 20. doi : 10.1111/j.1527-3458.2005.tb00033.x . PMC 6741764 . PMID 15867950 . Hempel R, Schupke H, McNeilly PJ, Heinecke K, Kronbach C, Grunwald C, et al. (May 1999). "Metabolism of retigabine (D-23129), a novel anticonvulsant" . Drug Metabolism and Disposition . 27 (5): 613– 622. doi : 10.1016/S0090-9556(24)15258-0 . PMID 10220491 . [ permanent dead link ] v t e Anticonvulsants ( N03 ) GABAergics GABA A R PAMs Barbiturates : Barbexaclone Metharbital Methylphenobarbital Pentobarbital Phenobarbital # Primidone ; Carbamates : Cenobamate Felbamate ; Benzodiazepines : Clobazam Clonazepam Clorazepate Diazepam # Lorazepam # Midazolam Nimetazepam Nitrazepam Temazepam ; Others: Bromide ( potassium bromide , sodium bromide ) Imepitoin Paraldehyde Stiripentol GABA-T inhibitors Fatty acids (and related): Valproate Valpromide Valproate pivoxil Vigabatrin Others GABAR agonists : Progabide ; GAT-1 inhibitors : Tiagabine Channel modulators Sodium blockers Hydantoins : Ethotoin Fosphenytoin Mephenytoin Phenytoin # ; Ureides : Acetylpheneturide Chlorphenacemide Phenacemide ‡ Pheneturide ; Fatty acids : Valproate Valpromide Valproate pivoxil ; Carboxamides : Carbamazepine # Eslicarbazepine acetate Oxcarbazepine ; Others: Lacosamide Lamot

Retigabine - Wikipedia

olum) Monastrol Nicotinic acid Nicotinamide Org 25,435 Phenytoin Propanidid Retigabine (ezogabine) Safranal Seproxetine Stiripentol Sulfonylalkanes (e.g., sulfonmethane (sulfonal) , tetronal , trional ) Terpenoids (e.g., borneol ) Topiramate Valerian constituents (e.g., isovaleric acid , isovaleramide , valerenic acid , valerenol ) Unsorted benzodiazepine site positive modulators: α-Pinene MRK-409 (MK-0343) TCS-1105 TCS-1205 See also: Receptor/signaling modulators • GABA receptor modulators • GABA metabolism/transport modulators Portal : Medicine Authority control databases : National United States Israel Retrieved from " https://en.wikipedia.org/w/index.php?title=Retigabine&oldid=1296296022 " Categories : Anticonvulsants Carbamates Potassium channel openers 4-Fluorophenyl compounds GABAA receptor positive allosteric modulators Withdrawn drugs Orphan drugs Hidden categories: CS1:Vancouver names with accept markup Articles with short description Short description is different from Wikidata Infobox drug with local INN variant ECHA InfoCard ID from Wikidata Drug has EMA link Articles containing unverified chemical infoboxes All articles with dead external links Articles with dead external links from June 2025 Articles with permanently dead external links This page was last edited on 19 June 2025, at 03:42 (UTC) . Text is available under the Creative Commons Attribution-ShareAlike 4.0 License ;
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Retigabine - Wikipedia

Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures - PMC

Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Official websites use .gov A .gov website belongs to an official
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the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Neuropsychiatr Dis Treat . 2011 Jul 7;7:409–414. doi: 10.2147/NDT.S14208 Search in PMC Search in PubMed View in NLM Catalog Add to search Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures Judith LZ Weisenberg Judith LZ Weisenberg 1 Department of Neurology, Washington University School of Medicine, St Louis, MO, USA Find articles by Judith LZ Weisenberg 1 , Michael Wong Michael Wong 1 Department of Neurology, Washington University School of Medicine, St Louis, MO, USA Find articles by Michael Wong 1, ✉ Author information Article notes Copyright and License information 1 Department of Neurology, Washington University School of Medicine, St Louis, MO, USA ✉ Correspondence: Michael Wong, Department of Neurology, Campus Box

The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy - PubMed

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Retigabine - Wikipedia

7–11 hours [ 1 ] Excretion Kidney (84%) Identifiers IUPAC name Ethyl N -[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate CAS Number 150812-12-7 PubChem CID 121892 IUPHAR/BPS 2601 DrugBank DB04953 ChemSpider 108740 UNII 12G01I6BBU KEGG D09569 ChEMBL ChEMBL41355 CompTox Dashboard ( EPA ) DTXSID40164615 ECHA InfoCard 100.158.123 Chemical and physical data Formula C 16 H 18 F N 3 O 2 Molar mass 303.337 g·mol −1 3D model ( JSmol ) Interactive image SMILES O=C(OCC)Nc1ccc(cc1N)NCc2ccc(F)cc2 InChI InChI=1S/C16H18FN3O2/c1-2-22-16(21)20-15-8-7-13(9-14(15)18)19-10-11-3-5-12(17)6-4-11/h3-9,19H,2,10,18H2,1H3,(H,20,21) Key:PCOBBVZJEWWZFR-UHFFFAOYSA-N Retigabine ( INN ) or ezogabine ( USAN ) is an anticonvulsant used as an adjunctive treatment for partial epilepsies in treatment-experienced adult patients. [ 2 ] 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. [ 3 ] [ 4 ] Retigabine works primarily as a potassium channel opener —that is, by activating a certain family of voltage-gated potassium channels in the brain. [ 5 ] [ 6 ] [ 7 ] This mechanism of action is unique among antiepileptic drugs, and may hold promise for

Retigabine - Wikipedia

development pipeline" . Epilepsy Research . 69 (3): 273– 294. doi : 10.1016/j.eplepsyres.2006.02.004 . PMC 1562526 . PMID 16621450 . ^ "Valeant Pharmaceuticals Announces Preliminary Results From Its Phase IIa Retigabine Study for the Treatment of Postherpetic Neuralgia (PHN)" (Press release). PRNewswire. 2009-08-24 . Retrieved 2011-06-13 . ^ "Retigabine NDA accepted for filing" (Press release). PRNewswire. 2009-12-30 . Retrieved 2010-07-19 . ^ a b Lowry F (2010-08-12). "Epilepsy drug exogabine gets green light from FDA Advisory Panel" . Medscape . Retrieved 2010-08-13 . ^ [No authors listed] (2010-06-25). "August 11, 2010: Peripheral and Central Nervous System Drugs Advisory Committee Meeting Announcement" . U.S. Food and Drug Administration . Archived from the original on July 3, 2010 . Retrieved 2010-07-19 . ^ U.S. Drug Enforcement Administration (15 December 2011). "Schedules of Controlled Substances: Placement of Ezogabine Into Schedule V" (PDF) . Federal Register . 76 (241). ^ World Health Organization (1996). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 76" (PDF) . WHO Drug Information . 10 (4): 215. Archived from the original (PDF) on June 27, 2004. ^ [No authors listed] (2005–2006). "Statement on a nonproprietary name adopted by the USAN council: Retigabine" (PDF) . American Medical Association . Retrieved 2010-07-19 . ^ [No authors listed] (2010). "Statement on a nonproprietary name adopted by the USAN council: Ezogabine" (PDF) . American Medical Association . Archived from the original (PDF) on 2012-04-02 . Retrieved 2010-07-19 . Further reading [ edit ] Blackburn-Munro G, Dalby-Brown W, Mirza NR, Mikkelsen JD, Blackburn-Munro RE (2005). "Retigabine: chemical synthesis to clinical

Retigabine - Wikipedia

channel opener —that is, by activating a certain family of voltage-gated potassium channels in the brain. [ 5 ] [ 6 ] [ 7 ] 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. Adverse effects [ edit ] The adverse effects found in the Phase II trial mainly affected the central nervous system, and appeared to be dose-related. [ 8 ] The most common adverse effects were drowsiness , dizziness , tinnitus and vertigo , confusion, and slurred speech . [ 9 ] Less common side effects included tremor , memory loss, gait disturbances, and double vision . [ 10 ] In 2013, FDA warned the public that Potiga (ezogabine) can cause blue skin discoloration and eye abnormalities characterized by pigment changes in the retina. FDA does not currently know if these changes are reversible. FDA is working with the manufacturer to gather and evaluate all available information to better understand these events. FDA will update the public when more information is available. [ 11 ] Psychiatric symptoms and difficulty urinating have also been reported, with most cases occurring in the first 2 months of treatment. [ 12 ] [ 13 ] Interactions [ edit ] 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 ] 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 ] Pharmacology [ edit ] Mechanism of action [ edit ] Retigabine acts as a neuronal KCNQ / Kv7 potassium channel opener , a mechanism of action markedly different from that of any current anticonvulsants. [ 5 ] [ 6 ] [ 7 ] This mechanism of action is similar to that of the chemically similar flupirtine , [ 15 ] which is used mainly for its analgesic properties. The

Retigabine - Wikipedia

The urinary safety profile and secondary renal effects of retigabine (ezogabine): a first-in-class antiepileptic drug that targets KCNQ (K(v)7) potassium channels - PubMed

The urinary safety profile and secondary renal effects of retigabine (ezogabine): a first-in-class antiepileptic drug that targets KCNQ (K(v)7) potassium channels - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Safety of retigabine in adults with partial-onset seizures after long-term exposure: focus on unexpected ophthalmological and dermatological events - PubMed

Safety of retigabine in adults with partial-onset seizures after long-term exposure: focus on unexpected ophthalmological and dermatological events - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures - PMC

iepileptogenic and antiictogenic effects of retigabine under conditions of rapid kindling: an ontogenic study. Epilepsia. 2008;49:1777–1786. doi: 10.1111/j.1528-1167.2008.01674.x. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 20. Biervert C, Schroeder BC, Kubisch C, et al. A potassium channel mutation in neonatal human epilepsy. Science. 1998;279:403–406. doi: 10.1126/science.279.5349.403. [ DOI ] [ PubMed ] [ Google Scholar ] 21. Charlier C, Singh NA, Ryan SG, et al. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet. 1998;18:53–55. doi: 10.1038/ng0198-53. [ DOI ] [ PubMed ] [ Google Scholar ] 22. Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet. 1998;18:25–29. doi: 10.1038/ng0198-25. [ DOI ] [ PubMed ] [ Google Scholar ] 23. Porter RJ, Partiot A, Sachedo R, Nohria C, Alves WM. Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures. Neurology. 2007;68:1197–1204. doi: 10.1212/01.wnl.0000259034.45049.00. [ DOI ] [ PubMed ] [ Google Scholar ] 24. Brodie MJ, Lerche H, Gil-Nagel A, et al. Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy. Neurology. 2010;75:1817–1824. doi: 10.1212/WNL.0b013e3181fd6170. [ DOI ] [ PubMed ] [ Google Scholar ] 25. French JA, Abou-Khalil BW, Leroy RF, et al. Randomized, double-

The urinary safety profile and secondary renal effects of retigabine (ezogabine): a first-in-class antiepileptic drug that targets KCNQ (K(v)7) potassium channels - PubMed

G compared with placebo, although most patients were able to continue with treatment. Specifically, there is an increased risk of urinary retention with RTG/EZG, with urinary hesitation representing the most frequently reported urinary retention-related AE. Potential secondary renal effects, which may be caused by an inability to empty the bladder, were evaluated. Crystals with a bilirubin-like appearance were detected in the urine of patients receiving RTG/EZG. Although investigations indicated that these crystals were not bilirubin, their composition remains undetermined. There was no causal association with urinary tract infections, and nephrolithiasis was uncommon. The reported clinical effects of RTG/EZG are consistent with its documented effects on bladder smooth muscle in preclinical studies. RTG/EZG should be used with caution in patients at risk of urinary retention. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy. PubMed Disclaimer Publication types Research Support, Non-U.S. Gov't Actions Search in PubMed Search in MeSH Add to Search Review Actions Search in PubMed Search in MeSH Add to Search MeSH terms Animals Actions Search in PubMed Search in MeSH Add to Search Anticonvulsants / adverse effects Actions Search in PubMed Search in MeSH Add to Search Carbamates / adverse effects Actions Search in PubMed Search in MeSH Add to Search Epilepsies, Partial / drug therapy Actions Search in PubMed Search in MeSH Add to Search Humans Actions Search in PubMed Search in MeSH Add to Search KCNQ Potassium Channels / metabolism Actions Search in PubMed Search in MeSH Add to Search Muscle, Smooth / drug effects Actions Search in PubMed Search in MeSH Add to Search Muscle, Smooth / metabolism Actions Search in PubMed Search in MeSH Add to Search Phenylenediamines / adverse effects Actions Search in PubMed Search in MeSH Add to Search Urinary Retention / chemically induced* Actions Search in PubMed Search in MeSH Add to Search Substances Anticonvulsants Actions Search in PubMed Search in MeSH Add to Search Carbamates Actions Search in PubMed Search in MeSH Add to Search KCNQ Potassium Channels Actions Search in PubMed Search in MeSH Add to Search Phenylenediamines Actions Search in PubMed Search in MeSH Add to Search ezogabine Actions Search in PubMed Search in MeSH Add to Search LinkOut - more resources Full Text Sources Wiley Medical

The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy - PubMed

ID Epilepsia Actions Search in PubMed Search in NLM Catalog Add to Search . 2012 Mar;53(3):412-24. doi: 10.1111/j.1528-1167.2011.03365.x. Epub 2012 Jan 5. Authors Martin J Gunthorpe 1 , Charles H Large , Raman Sankar Affiliation 1 New Frontiers Science Park, GlaxoSmithKline plc, Harlow, Essex, United Kingdom. martin.gunthorpe@gmail.com PMID: 22220513 DOI: 10.1111/j.1528-1167.2011.03365.x Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract The pharmacologic profile of retigabine [RTG (international nonproprietary name); ezogabine, EZG (U.S. adopted name)], is different from all currently approved antiepileptic drugs (AEDs). Its primary mechanism of action (MoA) as a positive allosteric modulator of KCNQ2-5 (K(v) 7.2-7.5) ion channels defines RTG/EZG as the first neuronal potassium (K(+)) channel opener for the treatment of epilepsy. KCNQ2-5 channels are predominantly expressed in neurons and are important determinants of cellular excitability, as indicated by the occurrence of human genetic mutations in KCNQ channels that underlie inheritable disorders including, in the case of KCNQ2/3, the syndrome of benign familial neonatal convulsions. In vitro pharmacologic studies demonstrate that the most potent action of RTG/EZG is at KCNQ2-5 channels, particularly heteromeric KCNQ2/3. Furthermore, mutagenesis and modeling studies have pinpointed the RTG/EZG binding site to a hydrophobic pocket near the channel gate, indicating how RTG/EZG can stabilize the open form of KCNQ2-5 channels; the absence of this site in KCNQ1 also provides a clear explanation for the inbuilt selectivity RTG/EZG has for potassium channels other than the KCNQ cardiac channel. KCNQ channels are active at the normal cell resting membrane potential (RMP) and contribute a continual hyperpolarizing influence that

Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures - PMC

Hiller A, Nguyen N, Strassburg C, et al. Retigabine N-glucuronidation and its potential role in enterohepatic circulation. Drug Metab Dispos. 1999;27:605–612. [ PubMed ] [ Google Scholar ] 31. Borlak J, Gasparic A, Locher M, Schupke H, Hermann R. 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;5:711–721. doi: 10.1016/j.metabol.2006.01.006. [ DOI ] [ PubMed ] [ Google Scholar ] 32. Ferron GM, Paul J, Fruncillo R, et al. Multiple-dose, linear, dose-proprotional, pharmacokinetics of retigabine in healthy volunteers. J Clin Pharmacol. 2002;42:175–182. doi: 10.1177/00912700222011210. [ DOI ] [ PubMed ] [ Google Scholar ] 33. Hermann R, Ferron GM, Erb K, et al. Effects of age and sex on the disposition of retigabine. Clin Pharmacol Ther. 2003;73:61–70. doi: 10.1067/mcp.2003.12. [ DOI ] [ PubMed ] [ Google Scholar ] 34. Hermann R, Knebel NG, Niebch G, Richards L, Borlak J, Locher M. Pharmacokinetic interaction between retigabine and lamotrigine in healthy subjects. Eur J Clin Pharmacol. 2003;58:795–802. doi: 10.1007/s00228-003-0558-6. [ DOI ] [ PubMed ] [ Google Scholar ] 35. Ferron GM, Patat A, Parks V, Rolan P, Troy SM. Lack of pharmacokinetic interaction between retigabine and phenobarbitone at steady-state in healthy subjects. Br J Clin Pharmacol. 2003;56:39–45. doi: 10.1046/j.1365-2125.2003.01825.x. [

Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures - PMC

igabine. J Neurosci. 2001;21:5535–5545. doi: 10.1523/JNEUROSCI.21-15-05535.2001. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 15. Rundfeldt C, Netzer R. Investigations into the mechanism of action of the new anticonvulsant retigabine. Interaction with GABAergic and glutamatergic neurotransmission and with voltage gated ion channels. Arzneimittelforschung. 2000;50:1063–1070. doi: 10.1055/s-0031-1300346. [ DOI ] [ PubMed ] [ Google Scholar ] 16. van Rijn CM, Willems-van Bree E. Synergy between retigabine and GABA in modulating the convulsant site of the GABAA receptor complex. Eur J Pharmacol. 2003;464:95–100. doi: 10.1016/s0014-2999(03)01426-2. [ DOI ] [ PubMed ] [ Google Scholar ] 17. Rostock A, Tober C, Rundfeldt C, et al. D-23129: a new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures. Epilepsy Res. 1996;23:211–223. doi: 10.1016/0920-1211(95)00101-8. [ DOI ] [ PubMed ] [ Google Scholar ] 18. De Sarro G, Di Paola ED, Conte G, Pasculli MP, De Sarro A. Influence of retigabine on the anticonvulsant activity of some antiepileptic drugs against audiogenic seizures in DBA/2 mice. Naynyn Schmiedebergs Arch Pharmacol. 2001;363:330–336. doi: 10.1007/s002100000361. [ DOI ] [ PubMed ] [ Google Scholar ] 19. Mazarati A, Wu J, Shin D, Kwon YS, Sankar R. Antiepileptogenic and antiictogenic effects of retigabine under conditions of rapid kindling: an ontogenic study. Epilepsia. 2008;49:1777–1786. doi: 10.1111/j.

Retigabine - Wikipedia

This was later adopted as the recommended International Nonproprietary Name (rINN) for the drug, and, in 2005 or 2006, the USAN Council —a program sponsored by the American Medical Association, the United States Pharmacopeial Convention, and the American Pharmacists Association that chooses nonproprietary names for drug sold in the United States—adopted the same name. [ 25 ] In 2010, however, the USAN Council rescinded its previous decision and assigned "ezogabine" as the United States Adopted Name for the drug. [ 26 ] The drug will thus be known as "ezogabine" in the United States and "retigabine" elsewhere. References [ edit ] ^ Ferron GM, Paul J, Fruncillo R, Richards L, Knebel N, Getsy J, Troy S (February 2002). "Multiple-dose, linear, dose-proportional pharmacokinetics of retigabine in healthy volunteers". Journal of Clinical Pharmacology . 42 (2): 175– 182. doi : 10.1177/00912700222011210 . PMID 11831540 . S2CID 5568963 . ^ "POTIGA (ezogabine) Tablets, CV. Full Prescribing Information" (PDF) . GlaxoSmithKline and Valeant Pharmaceuticals . Retrieved 4 June 2014 . ^ "GlaxoSmithKline: Advance notification of trobalt discontinuation" (PDF) . Archived from the original (PDF) on 2016-10-19. ^ "Epilepsy drug Trobalt (retigabine) to be discontinued" . epilepsysociety.org.uk . 14 September 2016. ^ a b Rundfeldt C (October 1997). "The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells". European Journal of Pharmacology . 336 ( 2– 3): 243– 249. doi : 10.1016/S0014-2999(97)01249-1 . PMID 9384239 . ^ a b Main MJ, Cryan JE, Dupere JR, Cox B, Clare JJ, Burbidge SA (August 2000). "Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine

Retigabine - Wikipedia

The urinary safety profile and secondary renal effects of retigabine (ezogabine): a first-in-class antiepileptic drug that targets KCNQ (K(v)7) potassium channels - PubMed

pileptic drug that targets KCNQ (K(v)7) potassium channels Neil Brickel et al. Epilepsia . 2012 Apr . Show details Display options Display options Format Abstract PubMed PMID Epilepsia Actions Search in PubMed Search in NLM Catalog Add to Search . 2012 Apr;53(4):606-12. doi: 10.1111/j.1528-1167.2012.03441.x. Epub 2012 Mar 16. Authors Neil Brickel 1 , Paul Gandhi , Kevan VanLandingham , Janet Hammond , Sarah DeRossett Affiliation 1 GlaxoSmithKline, Stockley Park, Middlesex, UK. neil.r.brickel@gsk.com PMID: 22428574 DOI: 10.1111/j.1528-1167.2012.03441.x Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Retigabine (RTG; international nonproprietary name)/ezogabine (EZG; North American adopted name), a first-in-class antiepileptic drug (AED) that reduces neuronal excitability primarily by enhancing the activity of KCNQ2/3 (K(v)7.2/7.3) potassium channels, has recently been approved by the European Medicines Agency and the U.S. Food and Drug Administration as adjunctive therapy in adults with partial-onset seizures. Much of the RTG/EZG safety profile will be familiar to health care professionals who are experienced with the clinical use of AEDs. RTG/EZG, as a potassium channel opener, also has a pharmacologic effect on smooth muscle of the urinary bladder. Consequently, the adverse event (AE) profile of RTG/EZG includes a potential risk of effects on the urinary system. This review summarizes the urinary safety profile and any secondary renal effects of RTG/EZG using data from patients in the pivotal controlled trials and the overall phase 2/3 clinical development program. Urinary AEs were reported more frequently in patients receiving RTG/EZG compared with placebo, although most patients were able to continue with treatment. Specifically, there is an increased risk of urinary retention with RTG/EZG, with urinary hesitation representing the most frequently reported urinary retention-related AE. Potential secondary renal

Retigabine - Wikipedia

that of any current anticonvulsants. [ 5 ] [ 6 ] [ 7 ] This mechanism of action is similar to that of the chemically similar flupirtine , [ 15 ] which is used mainly for its analgesic properties. 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. [ 16 ] A similar effect is observed on the homomeric Kv7.2 channel. [ 17 ] Pharmacokinetics [ edit ] 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. [ 14 ] Retigabine requires thrice-daily dosing due to its short half-life. [ 8 ] [ 9 ] [ 13 ] 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 ] History [ edit ] 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 . [ 18 ] Researchers hoped this wide-ranging activity would translate to studies in humans as well. [ 8 ] Clinical trials [ edit ] In a double-blind , randomized, placebo-controlled Phase II clinical trial, retigabine was

Retigabine - Wikipedia

MJ, Cryan JE, Dupere JR, Cox B, Clare JJ, Burbidge SA (August 2000). "Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine". Molecular Pharmacology . 58 (2): 253– 262. doi : 10.1124/mol.58.2.253 . PMID 10908292 . S2CID 11112809 . ^ a b Rogawski MA, Bazil CW (July 2008). "New molecular targets for antiepileptic drugs: alpha(2)delta, SV2A, and K(v)7/KCNQ/M potassium channels" . Current Neurology and Neuroscience Reports . 8 (4): 345– 352. doi : 10.1007/s11910-008-0053-7 . PMC 2587091 . PMID 18590620 . ^ a b c d Ben-Menachem E (2007). "Retigabine: has the orphan found a home?" . Epilepsy Currents . 7 (6): 153– 154. doi : 10.1111/j.1535-7511.2007.00209.x . PMC 2096728 . PMID 18049722 . ^ a b c Plosker GL, Scott LJ (2006). "Retigabine: in partial seizures". CNS Drugs . 20 (7): 601– 8, discussion 609–10. doi : 10.2165/00023210-200620070-00005 . PMID 16800718 . S2CID 23557118 . ^ a b Porter RJ, Partiot A, Sachdeo R, Nohria V, Alves WM (April 2007). "Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures". Neurology . 68 (15): 1197– 1204. doi : 10.1212/01.wnl.0000259034.45049.00 . PMID 17420403 . S2CID 24574886 . ^ "Potiga (Ezogabine): Drug Safety Communication" . Food and Drug Administration . Archived from the original on April 29, 2013. ^ a b Hitt E (2011-06-13). "FDA approves ezogabine for seizures in adults" .

Retigabine - Wikipedia

Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures - PMC

-negative KCNQ2 mutations. Neurology. 2007;69:2045–2053. doi: 10.1212/01.wnl.0000275523.95103.36. [ DOI ] [ PubMed ] [ Google Scholar ] 41. Blackburn-Munro G, Jensen BS. The anticonvulsant retigabine attenuates nociceptive behaviors in rat models of persistent and neuropathic pain. Eur J Pharmacol. 2003;460:109–116. doi: 10.1016/s0014-2999(02)02924-2. [ DOI ] [ PubMed ] [ Google Scholar ] 42. Munro G, Erichsen HK, Mirza NR. Pharmacological comparison of anticonvulsant drugs in animal models of persistent pain and anxiety. Neuropharmacology. 2007;53:609–618. doi: 10.1016/j.neuropharm.2007.07.002. [ DOI ] [ PubMed ] [ Google Scholar ] 43. Dencker D, Dias R, Pedersen ML, Husum H. Effect of the new antiepileptic drug retigabine in a rodent model of mania. Epilepsy Behav. 2008;12:49–53. doi: 10.1016/j.yebeh.2007.09.023. [ DOI ] [ PubMed ] [ Google Scholar ] 44. Hansen HH, Andreasen JT, Weikop P, Mirza M, Scheel-Kruger J, Mikkelsen JD. The neuronal KCNQ channel opener retigabine inhibits locomotor activity and reduces forebrain excitatory responses to the psychostimulants cocaine, methylphenidate and phencyclidine. Eur J Pharmacol. 2007;570:77–88. doi: 10.1016/j.ejphar.2007.05.029. [ DOI ] [ PubMed ] [ Google Scholar ] 45. Richter A, Sander SE, Rundfelt C. Antidystonic effects of Kv7 (KCNQ) channel openers in the dtsz mutant, an animal model of primary paroxysmal dystonia. Br J Pharmacol. 2006;149:747–753. doi: 10.1038/sj.bjp.0706878. [ DOI ] [ PMC free article ] [ PubMed ]

Safety of retigabine in adults with partial-onset seizures after long-term exposure: focus on unexpected ophthalmological and dermatological events - PubMed

. Electronic address: jerzy.2.daniluk@gsk.com. 6 GSK, Mumbai, India. Electronic address: kalpesh.k.joshi@gsk.com. 7 Instituto Nacional de Neurologia y Neurocirugia "Manuel Velasco Suarez", Tlalpan, Mexico. 8 Division of Neurology, Department of Medicine, Faculty of Medicine, Integrated Epilepsy Research Group, Khon Kaen University, Thailand. 9 Central Clinical Hospital #2 OAO RZD, Rehabilitation Department, Moscow, Russia; IM Sechenov First Moscow State Medical University (Sechenovskiy University), Ministry of Health, Russia. 10 GSK, Brentford, Middlesex, UK. Electronic address: james.5.cooper@gsk.com. PMID: 31731109 DOI: 10.1016/j.yebeh.2019.106580 Item in Clipboard Randomized Controlled Trial Safety of retigabine in adults with partial-onset seizures after long-term exposure: focus on unexpected ophthalmological and dermatological events Neil Brickel et al. Epilepsy Behav . 2020 Jan . Show details Display options Display options Format Abstract PubMed PMID Epilepsy Behav Actions Search in PubMed Search in NLM Catalog Add to Search . 2020 Jan:102:106580. doi: 10.1016/j.yebeh.2019.106580. Epub 2019 Nov 12. Authors Neil Brickel 1 , Karen Hewett 2 , Kirsty Rayner 3 , Susan McDonald 4 , Jeni De'Ath 1 , Jerzy Daniluk 5 , Kalpesh Joshi 6 , Marie Catherine Boll 7 , Somsak Tiamkao 8 , Olga Vorobyeva 9 , James Cooper 10 Affiliations 1 GSK, Uxbridge, Middlesex, UK. 2 GSK, Stevenage, Hertfordshire, UK. 3 Probabilitas Consulting Limited, Berkhamsted, Hertfordshire, UK. 4 GSK, Research Triangle Park, NC, USA. Electronic address: susan.a.mcdonald@gsk.com. 5 GSK, Warsaw, Poland. Electronic address: jerzy.2.daniluk@gsk.com. 6 GSK, Mumbai, India. Electronic address: kalpesh.k.j

Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures - PMC

. doi: 10.1124/mol.58.2.253. [ DOI ] [ PubMed ] [ Google Scholar ] 10. Schenzer A, Friedrich T, Pusch M, et al. Molecular determinants of KCNQ (Kv7) K+ channel sensitivity to the anticonvulsant retigabine. J Neurosci. 2005;25:5051–5060. doi: 10.1523/JNEUROSCI.0128-05.2005. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 11. Wuttke TV, Seebohm G, Bail S, Maljevic S, Lerche H. The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate. Mol Pharmacol. 2005;67:1009–1017. doi: 10.1124/mol.104.010793. [ DOI ] [ PubMed ] [ Google Scholar ] 12. 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. doi: 10.1124/mol.108.052282. [ DOI ] [ PubMed ] [ Google Scholar ] 13. Rundfeldt C, Netzer R. The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells transfected with human KCNQ2/3 subunits. Neurosci Lett. 2000;282:73–76. doi: 10.1016/s0304-3940(00)00866-1. [ DOI ] [ PubMed ] [ Google Scholar ] 14. Tatulian L, Delmas P, Abogadie FC, Brown DA. Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine. J Neurosci. 2001;21:5535–5545. doi: 10.1523/JNEUROSCI.21-15-05535.2001. [ DOI ] [ PMC free article ] [

Retigabine - Wikipedia

): Drug Safety Communication" . Food and Drug Administration . Archived from the original on April 29, 2013. ^ a b Hitt E (2011-06-13). "FDA approves ezogabine for seizures in adults" . Medscape . Retrieved 2011-06-13 . ^ a b c d e "Trobalt – Summary of Product Characteristics (SPC)" . electronic Medicines Compendium. 2011-05-05 . Retrieved 2011-06-13 . ^ a b c Luszczki JJ (2009). "Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions". Pharmacological Reports . 61 (2): 197– 216. doi : 10.1016/s1734-1140(09)70024-6 . PMID 19443931 . S2CID 72918370 . ^ Brown DA, Passmore GM (April 2009). "Neural KCNQ (Kv7) channels" . British Journal of Pharmacology . 156 (8): 1185– 1195. doi : 10.1111/j.1476-5381.2009.00111.x . PMC 2697739 . PMID 19298256 . ^ Corbin-Leftwich A, Mossadeq SM, Ha J, Ruchala I, Le AH, Villalba-Galea CA (March 2016). "Retigabine holds KV7 channels open and stabilizes the resting potential" . The Journal of General Physiology . 147 (3): 229– 241. doi : 10.1085/jgp.201511517 . PMC 4772374 . PMID 26880756 . ^ Villalba-Galea CA (2020-06-19). "Modulation of K V 7 Channel Deactivation by PI(4,5)P 2 " . Frontiers in Pharmacology . 11 : 895. doi : 10.3389/fphar.2020.00895 . PMC 7318307 . PMID 32636742 . ^ Rogawski MA (June 2006). "Diverse mechanisms of antiepileptic drugs in the development pipeline" . Epilepsy Research . 69 (3): 273– 294. doi : 10.1016/j.eplepsyres.2006.02.004 . PMC 1562526 . PMID 16621450 . ^

Retigabine - Wikipedia

Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures - PMC

Find articles by Michael Wong 1, ✉ Author information Article notes Copyright and License information 1 Department of Neurology, Washington University School of Medicine, St Louis, MO, USA ✉ Correspondence: Michael Wong, Department of Neurology, Campus Box 8111, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO 63110, USA, Tel +1 314 362 8713, Fax +1 314 362 9462, Email wong_m@wustl.edu Issue date 2011; Collection date 2011. © 2011 Weisenberg and Wong, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. PMC Copyright notice PMCID: PMC3140293 PMID: 21792307 Abstract Epilepsy is a common disease with significant morbidity and mortality. Approximately one-third of patients with epilepsy are refractory to available seizure medications, emphasizing the need to develop better drugs with novel mechanisms of action. Ezogabine, also known as retigabine, is a new potential adjunctive treatment for adults with intractable partial seizures. Ezogabine has a unique mechanism of action consisting of activating KCNQ2/3 (Kv7) potassium channels. Ezogabine has undergone a number of Phase II and III trials demonstrating efficacy at 600,900 and 1200 mg/day in a dose-dependent fashion. The most common adverse events with ezogabine are central nervous system effects, particularly dizziness and somnolence. Urologic symptoms, particularly urinary retention, represent a rare but unique side effect of ezogabine. Ezogabine is predominantly metabolized via glucuronidation. Its half-life is 8 hours, suggesting a need for three-times-a-day administration. Ezogabine exhibits minimal interactions with other seizure medications, except possibly lamotrigine. Ezogabine has potential for clinical applications in other medical conditions beyond epilepsy, such as neuropathic pain, neuromyotonia, and bipolar disease, but these are based primarily on experimental models. Keywords: antiepileptic drug, epilepsy, ezogabine Introduction Epilepsy is a common disease with a cumulative lifetime risk of at least 3%. 1 The majority of patients with epilepsy have partial seizures, accounting for about two-thirds

Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures - PMC

: antiepileptic drug, epilepsy, ezogabine Introduction Epilepsy is a common disease with a cumulative lifetime risk of at least 3%. 1 The majority of patients with epilepsy have partial seizures, accounting for about two-thirds of cases in epidemiologic studies in developed countries. 2 The burden of disease is also quite high, involving significant morbidity and mortality. Individuals with epilepsy in developed countries have an up to three-fold increase in mortality compared with the general population. 3 Adults with seizures have also been found to have lower levels of education, higher rates of unemployment as well as higher rates of physical ailments. 4 While the aim of epilepsy treatment is complete seizure control with minimal adverse events from medication, approximately one-third of patients will have persistent seizures despite antiepileptic drug (AED) treatment and can be classified as medically intractable. 5 , 6 Ezogabine is an ethyl N -(2-amino-4-[{4-fluorophenyl}methylamino]phenyl carbamate) ( Figure 1 ). Previously known as D-23129, it is also known by the international nonproprietary name of retigabine in Europe and most of the world, but the adopted name in the United States is ezogabine. This drug was recently approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for adjunctive treatment of partial-onset seizures in adults. It appears to work by a unique mechanism of action compared with other currently available AEDs. Figure 1. Open in a new tab Chemical structure of ezogabine. Mechanism of action Ezogabine exerts its anticonvulsant effects through a novel mechanism of action that is unique among existing AEDs. In particular, ezogabine activates potassium currents in neurons, 7 which should lead to hyperpolarization of the membrane potential and decreased neuronal excitability under physiological conditions. On the molecular level, ezogabine enhances the activation of a specific heteromeric potassium channel, consisting of KCNQ2 or KCNQ3 channel subunits, a member of the Kv7 family of potassium channels. 8 , 9 Ezogabine binds to the activation gate or within the pore of the channel itself to stabilize the channel in the open position. 10 – 12 KCNQ2/3 channels mediate

Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures - PMC

to assess the potential efficacy of ezogabine for the pediatric population and for other seizure types or epilepsy syndromes, such as generalized seizures. Safety Data on the safety and side effects of ezogabine were also derived from the three placebo-controlled, multicenter studies testing ezogabine as adjunctive therapy in adult patients with refractory partial seizures ( Table 2 ). In the first study, common adverse events (>10%) could be mostly categorized as central nervous system (CNS) effects and occurred more frequently in the ezogabine arms. These included somnolence, confusion, dizziness, tremor, amnesia, thinking abnormal, vertigo, and speech disorder. 23 In the second study, common adverse effects (>10%) all could be categorized again as CNS effects and were described as dizziness, somnolence, headache, and fatigue. 24 In the third study, CNS effects were again the most common, with 40.5% complaining of dizziness and 31.4% complaining of somnolence in the ezogabine group. 25 Additional common treatment emergent adverse events were fatigue, confusion, dysarthria, ataxia, blurred vision, and tremor. Nausea was also reported in 10.5% of ezogabine patients compared with 6.6% in the placebo group. 25 This was higher than seen in the RESTORE 2 study, at 6.1% in the 600 mg/day group and 6.7% in the 900 mg/day group. 24 Urinary tract infections were seen in 11.8% of subjects on ezogabine compared with 8.6% in the placebo group. 25 Table 2. Summary of common adverse events (>10% of patients) reported in ezogabine-treated patients from randomized, double-blind, placebo-controlled trials as adjunctive treatment of refractory partial seizures in adults Dizziness Somnolence Fatigue Confusion Headache Dysarthria Tremor Vertigo Ataxia Amnesia Thinking abnormal Speech disorder Blurry vision Asthenia Nausea Urinary tract infection Open in a new tab Source: Porter et al, 23 Brodie et al, 24 French et al. 25 As ezogabine has been demonstrated to have effects on bladder function in a rat model, extra attention was paid to urinary system side effects in RESTORE 1

Retigabine - Wikipedia

entin enacarbil Imagabalin Mirogabalin PD-200,347 PD-217,014 PD-299,685 Phenibut Pregabalin Others/unsorted: Bencyclane Berbamine Bevantolol Canadine Carboxyamidotriazole Cycleanine Dauricine Dimeditiapramine Diproteverine Enpiperate Eperisone Elpetrigine Ethadione Ethanol (alcohol) Ethosuximide Fasudil Fendiline Fostedil Imepitoin JTV-519 Lidoflazine Magnesium Manoalide Mesuximide Monatepil Naftopidil Ochratoxin A Osthol Otilonium bromide Paramethadione Phensuximide Pinaverium bromide Prenylamine Rhynchophylline Sesamodil Silperisone Sipatrigine Terodiline Tetrandrine Tolperisone Trimethadione Valperinol Activators L-type-selective : Bay K8644 Potassium VGKCs Tooltip Voltage-gated potassium channels Blockers 3,4-Diaminopyridine (amifampridine) 4-Aminopyridine (fampridine/dalfampridine) Adekalant Almokalant Amiodarone Azimilide Bretylium Bunaftine Charybdotoxin Clamikalant Conotoxins Dalazatide Dendrotoxin Dofetilide Dronedarone E-4031 Hanatoxin HgeTx1 HsTx1 Ibutilide Inakalant Kaliotoxin Linopirdine Lolitrem B Maurotoxin Nifekalant Notoxin Paxilline Pinokalant Quinidine ShK-186 Sotalol Tedisamil Terikalant Tetraethylammonium Vernakalant hERG (KCNH2, K v 11.1)-specific: Ajmaline Amiodarone AmmTX3 Astemizole Azaspiracid AZD1305 Azimilide Bedaquiline BeKm-1 BmTx3 BRL-32872 Chlorpromazine Cisapride Clarithromycin Darifenacin Dextropropoxyphene

Retigabine - Wikipedia

Safety of retigabine in adults with partial-onset seizures after long-term exposure: focus on unexpected ophthalmological and dermatological events - PubMed

Sunday The first Monday The first Tuesday The first Wednesday The first Thursday The first Friday The first Saturday The first day The first weekday Which day? Sunday Monday Tuesday Wednesday Thursday Friday Saturday Report format: Summary Summary (text) Abstract Abstract (text) PubMed Send at most: 1 item 5 items 10 items 20 items 50 items 100 items 200 items Send even when there aren't any new results Optional text in email: Save Cancel Create a file for external citation management software Create file Cancel Your RSS Feed Name of RSS Feed: Number of items displayed: 5 10 15 20 50 100 Create RSS Cancel RSS Link Copy Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Permalink Permalink Copy Display options Display options Format Abstract PubMed PMID Page navigation Title & authors Abstract Publication types MeSH terms Substances LinkOut - more resources Title & authors Abstract Publication types MeSH terms Substances LinkOut - more resources Randomized Controlled Trial Epilepsy Behav Actions Search in PubMed Search in NLM Catalog Add to Search . 2020 Jan:102:106580. doi: 10.1016/j.yebeh.2019.106580. Epub 2019 Nov 12. Safety of retigabine in adults with partial-onset seizures after long-term exposure: focus on unexpected ophthalmological and dermatological events Neil Brickel 1 , Karen Hewett 2 , Kirsty Rayner 3 , Susan McDonald 4 , Jeni De'Ath 1 , Jerzy Daniluk 5 , Kalpesh Joshi 6 , Marie Catherine Boll 7 , Somsak Tiamkao 8 , Olga Vorobyeva 9 , James Cooper 10 Affiliations Expand Affiliations 1 GSK, Uxbridge, Middlesex, UK. 2 GSK, Stevenage, Hertfordshire, UK. 3 Probabilitas Consulting Limited, Berkhamsted, Hertfordshire, UK. 4 GSK, Research Triangle Park, NC, USA. Electronic address: susan.a.mcdonald@gsk.com. 5 GSK, Warsaw, Poland. Electronic address: jerzy.2.daniluk@gsk.com. 6 GSK, Mumbai, India. Electronic address: kalpesh.k.joshi@gsk.com. 7 Instituto Nacional

Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures - PMC

3 potassium channels have been identified as the cause of cases of benign familial neonatal convulsions. 20 – 22 Defective potassium channel function represents a rational mechanistic explanation for brain hyperexcitability and seizures in this inherited epilepsy syndrome. Since ezogabine enhances the function of KCNQ2/3 channels, ezogabine represents a rare example in which a seizure medication may directly target the underlying molecular defect causing a specific type of epilepsy. Efficacy There have been three placebo-controlled, multicenter studies to assess safety and efficacy in adults ( Table 1 ). All of these studies were performed on patients aged 18–75. In all of these studies, ezogabine was used as adjunctive therapy in patients with refractory partial seizures, who were already on at least one or two other AEDs, such as valproate, carbamazepine, phenytoin, topiramate, lamotrigine, gabapentin, oxcarbazepine, benzodiazepines, or barbiturates. The first of these studies looked at multiple dosing schedules, 600, 900, and 1200 mg/day, administered three times daily. 23 Based on this study, the FDA recommended two confirmatory studies. RESTORE 2 addressed dosages of 600 and 900 mg/day administered three times daily, 24 and RESTORE 1 addressed the dosage of 1200 mg/day divided three times daily. 25 Table 1. Summary of efficacy data from randomized, double-blind, placebo-controlled trials of ezogabine as adjunctive treatment of refractory partial seizures in adults Study/outcome measure Placebo Ezogabine 600 mg/d 900 mg/d 1200 mg/d Porter et al 23 n = 96 n = 99 n = 95 n = 106 Median change in seizure frequency, % −13.1 −23.4 a −29.3 a −35.2 a Patients with >50% seizure reduction, % 15.6 23.2 31.6 a 33.0 a RESTORE 2 (Brodie et al 24 ) n = 170 n = 179 n = 175 Median change in seizure frequency, % −15.9 −27.9 a −39.9 a Patients with >50% seizure reduction, % 18.9 38.6 a 47.0 a RESTORE 1 (French et al 25 ) n = 152 n = 153 Median change

Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures - PMC

: Porter et al, 23 Brodie et al, 24 French et al. 25 As ezogabine has been demonstrated to have effects on bladder function in a rat model, extra attention was paid to urinary system side effects in RESTORE 1 and 2. 26 , 27 In RESTORE 2, three patients on ezogabine experienced chromaturia (occasional reddish-brown discoloration of urine) and three patients exited the study because of adverse events of the urinary tract (one nephritis and two urinary retention). 24 In RESTORE 1, it was observed that 15 of the ezogabine-treated patients had increased post-void residual volumes of >100 mL compared with six of the placebo-treated patients. 25 Other adverse events observed included urinary tract infection, urinary hesitation, dysuria, and chromaturia, all of which were infrequent but occurred more commonly in the ezogabine-treated group than placebo. 25 In summary, common adverse events of ezogabine are CNS effects, with the most common of these being dizziness and somnolence. All adverse events appeared to have some dose dependency. No significant cardiac, hematologic, or liver adverse events have been reported. 23 – 25 Some attention should be paid to potential adverse effects on the urinary tract. There are no reported safety data in the pediatric population. Pharmacology Ezogabine is metabolized primarily in the liver by acetylation to the mono-acetylated metabolite AWD21–360 and more significantly by glucuronidation to an N-glucuronide 28 – 31 with subsequent predominant renal clearance. The cytochrome P450 system does not appear to play a significant role in the metabolism of ezogabine. 29 Glucuronidation appears to be predominantly by the UGT1A1, UGT1A9, and less so, UGT1A4 enzymes. 30 , 31 A variety of studies have assessed the pharmacokinetics of ezogabine with the majority of the data being obtained in a study by Ferron et al that assessed the pharmacokinetics of ezogabine at multiple doses up to 700 mg/day in 45 healthy male volunteers. 32 It is rapidly absorbed after oral administration, with a peak plasma concentration at 1.5 hours. 32 With food, maximal plasma concentration is delayed to approximately 2 hours. Mean terminal half-life was 8