Retigabine ( INN) or ezogabine ( USAN) is an

anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

used as an adjunctive treatment for

partial Partial may refer to: Mathematics *Partial derivative, derivative with respect to one of several variables of a function, with the other variables held constant ** ∂, a symbol that can denote a partial derivative, sometimes pronounced "partial d ...

epilepsies in treatment-experienced adult patients. The drug was developed by Valeant Pharmaceuticals and

GlaxoSmithKline GSK plc (an acronym from its former name GlaxoSmithKline plc) is a British Multinational corporation, multinational Pharmaceutics, pharmaceutical and biotechnology company with headquarters in London. It was established in 2000 by a Mergers an ...

. It was approved by the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

under the trade name Trobalt on March 28, 2011, and by the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA), under the trade name Potiga, on June 10, 2011. Production was discontinued in June 2017. Retigabine works primarily as a potassium channel opener—that is, by activating a certain family of

voltage-gated potassium channel Voltage-gated potassium channels (VGKCs) are potassium channel, transmembrane channels specific for potassium and Voltage-gated ion channel, sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a ...

s in the brain. This

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

is unique among antiepileptic drugs, and may hold promise for the treatment of other neurologic conditions, including

tinnitus Tinnitus is a condition when a person hears a ringing sound or a different variety of sound when no corresponding external sound is present and other people cannot hear it. Nearly everyone experiences faint "normal tinnitus" in a completely ...

migraine Migraine (, ) is a complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea, and light and sound sensitivity. Other characterizing symptoms may includ ...

and

neuropathic pain Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuo ...

. The manufacturer withdrew retigabine from clinical use in 2017.

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 Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

and

vertigo Vertigo is a condition in which a person has the sensation that they are moving, or that objects around them are moving, when they are not. Often it feels like a spinning or swaying movement. It may be associated with nausea, vomiting, perspira ...

, confusion, and slurred speech. Less common side effects included

tremor A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...

, memory loss,

gait Gait is the pattern of Motion (physics), movement of the limb (anatomy), limbs of animals, including Gait (human), humans, during Animal locomotion, locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on s ...

disturbances, and double vision. 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. Psychiatric symptoms and difficulty urinating have also been reported, with most cases occurring in the first 2 months of treatment.

Interactions

Retigabine appears to be free of

drug interaction In pharmaceutical sciences, drug interactions occur when a drug's mechanism of action is affected by the concomitant administration of substances such as foods, beverages, or other drugs. A popular example of drug–food interaction is the effect ...

s with most commonly used anticonvulsants. It may increase metabolism of lamotrigine (Lamictal), whereas phenytoin (Dilantin) and carbamazepine (CBZ, Tegretol) increase the clearance of retigabine. Concomitant use of retigabine and

digoxin Digoxin (better known as digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart disease, heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. ...

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.

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. 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.

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 In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

(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. Retigabine is metabolized in the liver, by ''N''-

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...

and

acetylation : In chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply ''acetates''. Deacetylation is the opposite react ...

. The

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

system is not involved. Retigabine and its metabolites are excreted almost completely (84%) by the kidneys.

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 The amygdala (; : amygdalae or amygdalas; also '; Latin from Greek language, Greek, , ', 'almond', 'tonsil') is a paired nucleus (neuroanatomy), nuclear complex present in the Cerebral hemisphere, cerebral hemispheres of vertebrates. It is c ...

, pentylenetetrazol, kainate, NMDA, and picrotoxin. Researchers hoped this wide-ranging activity would translate to studies in humans as well.

Clinical trials

In a

double-blind In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expec ...

, 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. 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".

Regulatory approval

The U.S. Food and Drug Administration accepted Valeant's

New Drug Application The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial ...

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 Urinary retention is an inability to completely empty the bladder. Onset can be sudden or gradual. When of sudden onset, symptoms include an inability to urinate and lower abdominal pain. When of gradual onset, symptoms may include urinary incont ...

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 The Drug Enforcement Administration (DEA) is a Federal law enforcement in the United States, United States federal law enforcement agency under the U.S. Department of Justice tasked with combating illicit Illegal drug trade, drug trafficking a ...

. In December 2011, the U.S.

(DEA) placed the substance into Schedule V of the

Controlled Substances Act The Controlled Substances Act (CSA) is the statute establishing federal government of the United States, federal drug policy of the United States, U.S. drug policy under which the manufacture, importation, possession, use, and distribution of ...

(CSA), the category for substances with a comparatively low potential for abuse. This became effective 15 December 2011.

Name

The International Nonproprietary Name "retigabine" was initially published as being under consideration by WHO in 1996. 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. In 2010, however, the USAN Council rescinded its previous decision and assigned "ezogabine" as the United States Adopted Name for the drug. The drug will thus be known as "ezogabine" in the United States and "retigabine" elsewhere.