Retigabine

303.3314232

303.33

200-835-2

12G01I6BBU

2779

DTXSID40164615

White to slightly colored crystalline powder

N03AX21|N - Nervous system

76.4

3.57 (est)

white to light brown

1.307±0.06 g/cm3(Predicted)

138-145 deg C

430.0±45.0 °C(Predicted)

2℃

1.656

DMSO: >15mg/mL

room temp

1.3X10-7 mm Hg at 25 deg C (est)

Odorless

Tasteless

Henry's Law constant = 8.93X10-10 atm-cu m/mol at 25 °C (est)

10.8|pKa = 3.7 (basic)|pKa = 10.8

Non-hygroscopic|Hydroxyl radical reaction rate constant = 2.1X10-10 cu cm/molec-sec at 25 °C (est)

UN 2811 6.1 / PGIII

3

23-25-50/53-36-20/21/22-11

45-60-61-36/37-16-26

T,N,Xn,F,Xi

P305 + P351 + P338

H319-H413

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Contaminated packaging: Dispose of as unused product.

Strong oxidizing agents

Schedule V shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. ... Depressants. Unless specifically exempted or excluded or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances having a depressant effect on the central nervous system, including its salts: Ezogabine (DEA Code Number: 2779) is included on this list.|The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ezogabine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.|Drug Name: Potiga; FDA Application No.: (NDA) 022345; Active Ingredient: Ezogabine; Company: Glaxosmithkline; Original Approval or Tentative Approval Date: June 10, 2011; Chemical Type: 1 New molecular entity (NME); Review Classification: Standard review drug.

|Warning|H400 (98.48%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]|P273, P391, and P501|Aggregated GHS information provided by 198 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Hand protection: Handle with gloves.|Personal protective equipment: Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).|Skin and body protection: impervious clothing, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Eye protection: Safety glasses with side-shields conforming to EN166 Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Not flammable or combustible.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. Special protective equipment for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

Personal precautions: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.|Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.|Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

Lethal Dose, acute, oral, rat = 100 mg/kg; Lethal Dose, chronic, oral, rat = 5.1 mg/kg/day, 90-day; Most common adverse effects that lead to discontinuation of therapy include dizziness and somnolence.

Limited data are available on the hepatotoxicity of ezogabine. In clinical trials, therapy with ezogabine was not associated with an increased frequency of serum aminotransferase elevations as compared to placebo treatment, and there were no instances of clinically apparent liver injury. No individual case reports of ezogabine hepatotoxicity have been published since its more wide spread clinical availability. Thus, clinically apparent liver injury due to ezogabine must be rare, if it occurs at all.

In healthy individuals, concomitant administration of ezogabine (daily dosage of 600 mg) and lamotrigine (daily dosage of 200 mg) resulted in an 18% decrease in lamotrigine AUC and a 22% increase in clearance of lamotrigine. Mean half-life and AUC of ezogabine were increased by 7.5 and 15%, respectively. The observed pharmacokinetic interaction was considered to be modest, and thought to be a result of competition for renal elimination rather than competition for glucuronidation. In addition, a population pharmacokinetic analysis of data from phase 3 clinical studies showed no evidence of any substantial interaction between ezogabine and lamotrigine. Studies in human liver microsomes suggest that lamotrigine, even at high concentrations, does not affect the glucuronidation of ezogabine. No dosage adjustment is necessary in patients receiving concomitant ezogabine and lamotrigine therapy.|Data from a phase 2 study indicate that ezogabine concentrations may be reduced with concomitant administration of carbamazepine or phenytoin. In this study, ezogabine clearance was increased by 28-33% when administered with carbamazepine or phenytoin; peak plasma concentrations and AUC of ezogabine were decreased by 18-23 and 31-34%, respectively. Carbamazepine and phenytoin pharmacokinetics were unaffected. If carbamazepine or phenytoin therapy is initiated in a patient receiving ezogabine, an ezogabine dosage increase should be considered; conversely, a reduction in ezogabine dosage should be considered when carbamazepine or phenytoin is discontinued.|Concomitant use of drugs that affect urinary voiding, such as anticholinergic agents, can increase the risk of urinary retention associated with ezogabine. Patients receiving such concomitant therapy should be closely monitored. In addition, a comprehensive evaluation of urologic symptoms prior to and during ezogabine therapy may be appropriate.|In healthy individuals, concomitant use of alcohol (1 g/kg of ethanol over 20 minutes) and ezogabine (single 200-mg dose) increased peak plasma concentrations and area under the plasma concentration-time curve (AUC) of ezogabine by approximately 23 and 37%, respectively, and was associated with an increased incidence of blurred vision. The pharmacokinetics of ethanol were not affected. Patients receiving ezogabine should be advised that alcohol consumption may potentiate some of the dose-related adverse effects associated with the drug (e.g., somnolence, fatigue).|For more Interactions (Complete) data for Ezogabine (9 total), please visit the HSDB record page.

Approximately 80% protein bound.

EXPERIMENTAL: In lactating rats, less than 2% of administrated dose was recovered in milk and tissues of the pups at >24 hours post-dosing. The majority of radioactivity (up to 85 %) in rat milk was related to a rat specific metabolite with a milk/plasma ratio of 35:1.

Adjuvant treatment of partial-onset seizures.|FDA Label|Trobalt is indicated as adjunctive treatment of drug-resistant partial-onset seizures with or without secondary generalisation in patients aged 18 years or older with epilepsy, where other appropriate drug combinations have proved inadequate or have not been tolerated.|Treatment of epilepsy with partial-onset seizures, Treatment of Lennox-Gastaut syndrome

Ezogabine, which is known as retigabine in Europe, is a unique anticonvulsant used largely as an adjunctive agent in the treatment of partial seizures. Therapy with ezogabine has not been associated with serum aminotransferase elevations, and clinically apparent liver injury from ezogabine has yet to be reported and must be rare, if it occurs at all.

Anticonvulsants

Anticonvulsants; Membrane Transport Modulators|Potiga is indicated as adjunctive treatment of partial-onset seizures in patients aged 18 years and older who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal abnormalities and potential decline in visual acuity. /Included in US product label/

/BOXED WARNING/ WARNING: RETINAL ABNORMALITIES AND POTENTIAL VISION LOSS. Potiga can cause retinal abnormalities with funduscopic features similar to those seen in retinal pigment dystrophies, which are known to result in damage to the photoreceptors and vision loss. Some patients with retinal abnormalities have been found to have abnormal visual acuity. It is not possible to determine whether Potiga caused this decreased visual acuity, as baseline assessments are not available for these patients. Approximately one third of the patients who had eye examinations performed after approximately 4 years of treatment were found to have retinal pigmentary abnormalities. An earlier onset cannot be ruled out, and it is possible that retinal abnormalities were present earlier in the course of exposure to Potiga. The rate of progression of retinal abnormalities and their reversibility are unknown. Potiga should only be used in patients who have responded inadequately to several alternative treatments and for whom the benefits outweigh the potential risk of vision loss. Patients who fail to show substantial clinical benefit after adequate titration should be discontinued from Potiga. All patients taking Potiga should have baseline and periodic (every 6 months) systematic visual monitoring by an ophthalmic professional. Testing should include visual acuity and dilated fundus photography. Additional testing may include fluorescein angiograms (FA), ocular coherence tomography (OCT), perimetry, and electroretinograms (ERG). If retinal pigmentary abnormalities or vision changes are detected, Potiga should be discontinued unless no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss.|Skin discoloration and eye abnormalities characterized by pigment changes in the retina have been reported in patients receiving ezogabine. In the cases reported to date, the skin discoloration appeared as blue pigmentation, predominantly on or around the lips or in the nail beds of the fingers or toes; however, more widespread involvement of the face and legs has also been reported. In addition, scleral and conjunctival discoloration (on the white of the eye and inside the eyelids) has been observed. The blue skin discoloration generally occurred following 4 years of treatment with ezogabine, but has been observed sooner in some patients. In some cases, retinal abnormalities were observed in the absence of skin discoloration. It is not yet known if the retinal and skin changes are reversible. All patients receiving ezogabine should have a baseline or initial eye examination followed by periodic eye examinations that should include visual acuity testing and dilated fundus photography, and may include fluorescein angiograms (FA), ocular coherence tomography (OCT), perimetry, and electroretinograms (ERG). If ophthalmologic changes are observed, ezogabine should be discontinued unless no other treatment options are available. If a patient develops skin discoloration, serious consideration should be given to changing to an alternative anticonvulsant agent.|Suicidal behavior and ideation have been reported in patients receiving anticonvulsants, including ezogabine. The US Food and Drug Administration (FDA) has alerted healthcare professionals about an increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants compared with placebo. The analysis of suicidality reports from placebo-controlled studies involving 11 anticonvulsants (i.e., carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%). This increased suicidality risk was observed as early as one week after beginning therapy and continued through 24 weeks. Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions. Based on the current analysis of the available data, the FDA recommends that clinicians inform patients, their families, and caregivers of the potential for an increased risk of suicidality with anticonvulsant therapy and that all patients currently receiving or beginning therapy with any anticonvulsant be closely monitored for notable changes that may indicate the emergence or worsening of suicidal thoughts or behavior or depression. Symptoms such as anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality. Clinicians who prescribe ezogabine or any other anticonvulsant should balance the risk of suicidality with the clinical need for the drug and the risk associated with untreated illness. Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. If suicidal thoughts or behaviors emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.|As with all anticonvulsant agents, ezogabine therapy should be withdrawn gradually whenever possible to minimize the risk of increased seizure frequency. When discontinuing therapy, dosage should be reduced over a period of at least 3 weeks unless safety concerns require more rapid withdrawal.|For more Drug Warnings (Complete) data for Ezogabine (19 total), please visit the HSDB record page.

As compared to other antiepileptic agents, ezogabine is unique in that it selectively activates potassium ion channels Kv 7.2-Kv7.5 and not cardiac Kv 7.1, thereby avoiding cardiac side effects. The antiepileptics, as a drug class, are routinely used in the treatment of a number of disease states in addition to epilepsy. Ezogabine is highly efficacious in a broad-spectrum of in vivo epilepsy and seizure models. A comparison of antiepileptic form activity of ezogabine with that of conventional anticonvulsants in in vitro models suggests that retigabine is especially likely to be useful in the treatment of pharmacoresistant epilepsy. Retigabine clearly attenuates pain-like behaviors in various animal models of neuropathic pain; it may also prove to be useful in treatment of clinical anxiety disorders. Clinical data obtained thus far indicate that retigabine is well tolerated in humans when titrated up to its therapeutic dose range. No tolerance, drug dependence, or withdrawal liability has been reported. Thus, retigabine may prove to be useful in the treatment of a diverse range of disease states in which neuronal hyperexcitability is a common underlying factor.

Agents that affect ION PUMPS; ION CHANNELS; ABC TRANSPORTERS; and other MEMBRANE TRANSPORT PROTEINS. (See all compounds classified as Membrane Transport Modulators.)|Drugs used to prevent SEIZURES or reduce their severity. (See all compounds classified as Anticonvulsants.)

Rapidly absorbed and distributed, with an absolute oral bioavailability of 60%. Pharmacokinetics of ezogabine suggest first-order kinetics. Tmax, single oral dose = 30-120 minutes; Time to steady state = 3 days|Urine (85%, 36% of total dose as unchanged drug, 18% of total dose as NAMR) and feces (14%, 3% of total dose as unchanged drug)|8.7 L/kg|0.58 - 0.76 L/h·kg. Clearance may differ between ethnic groups with Black Americans having 20% lower clearance than Caucasian Americans.|In all tested species, retigabine was rapidly absorbed from the gastro-intestinal tract following single PO administration (< 2 hr). Dietary dosing in rodents expectedly resulted in substantially lower Cmax values obtained several hours after treatment.|In rat and dogs studies evaluating the excretion of retigabine and the N-acetyl metabolite of ezogabine (NAMR) showed that retigabine and metabolites were excreted in both faeces and urine, with an approximate 2:1 faeces:urine split of the eliminated dose. Studies with bile duct cannulated rats showed that a major part of the retigabine-related radioactivity in faeces originated from the bile. NAMR was excreted to a greater extent in the urine, i.e., approximately one-half to two-third of the dose. Elimination patterns were similar following both PO and IV dosing, and the elimination of drug via the faeces following IV dosing was in accordance with significant biliary excretion.|Data from in vitro studies indicate that ezogabine and the N-acetyl metabolite of ezogabine (NAMR) are approximately 80% and 45% bound to plasma protein, respectively. Clinically significant interactions with other drugs through displacement from proteins are not anticipated. The steady-state volume of distribution of ezogabine is 2 to 3 L/kg following intravenous dosing, suggesting that ezogabine is well distributed in the body.|After both single and multiple oral doses, ezogabine is rapidly absorbed with median time to maximum plasma concentration (Tmax) values generally between 0.5 and 2 hours. Absolute oral bioavailability of ezogabine relative to an intravenous dose of ezogabine is approximately 60%. High-fat food does not affect the extent to which ezogabine is absorbed based on plasma AUC values, but it increases peak concentration (Cmax) by approximately 38% and delays Tmax by 0.75 hour.|For more Absorption, Distribution and Excretion (Complete) data for Ezogabine (9 total), please visit the HSDB record page.

Ezogabine is metabolized exclusively via phase II hepatic N-glucurodination and acetylation. N-glucurodination is the major metabolic pathway of the two and form two major N-glucuronide metabolites. The enzymes involved are UGT1A1, 1A9, 1A4, and 1A3. However, the product of the N-acetyl pathway is a weak, active metabolite referred to as NAMR. The enzyme that is involved in the N-acetyl pathway is called N-acetyltransferase 2. The pharmacokinetics of NAMR and ezogabine are similar. The cytochrome P450 enzyme system is not involved with the metabolism of ezogabine.|The primary routes of retigabine metabolism were dominated by phase II processes involving hydrolysis/N-acetylation to form the N-acetyl metabolite of ezogabine (NAMR) and N-glucuronidation of retigabine and NAMR. There was no evidence of direct oxidative metabolism of retigabine in any species. There was no evidence of NAMR formation in the dog and little NAMR formation in the Cynomolgus monkey. All evaluated species formed N-glucuronides of retigabine. N-glucoside metabolites of RTG were also observed in dog and humans.|Ezogabine is extensively metabolized primarily via glucuronidation and acetylation in humans. A substantial fraction of the ezogabine dose is converted to inactive N-glucuronides, the predominant circulating metabolites in humans. Ezogabine is also metabolized to the N-acetyl metabolite of ezogabine (NAMR) that is also subsequently glucuronidated. NAMR has antiepileptic activity, but it is less potent than ezogabine in animal seizure models. Additional minor metabolites of ezogabine are an N-glucoside of ezogabine and a cyclized metabolite believed to be formed from NAMR. In vitro studies using human biomaterials showed that the N-acetylation of ezogabine was primarily carried out by NAT2, while glucuronidation was primarily carried out by UGT1A4, with contributions by UGT1A1, UGT1A3, and UGT1A9. In vitro studies showed no evidence of oxidative metabolism of ezogabine or NAMR by cytochrome P450 enzymes. Coadministration of ezogabine with medications that are inhibitors or inducers of cytochrome P450 enzymes is therefore unlikely to affect the pharmacokinetics of ezogabine or NAMR.|Retigabine has known human metabolites that include retigabine N2-glucuronide.

Terminal half-life = 7.5 hours|A high variability was generally observed in the elimination half-life values of retigabine. The half-life was in the range of 1.4-9 hr in rats, 4-22 hr in rabbits, 0.9-20 hr in dogs, compared to 6-10 hr in humans. Thus, rats were generally having lower values for half-life than rabbits, dogs and humans.|In pregnant rats, the tissue distribution pattern was similar in dams and fetuses but the tissue exposure in fetal tissue was lower and more uniform with no high concentration organs as seen in the dams. The tissue elimination half lives in dams were between 4-18 hours and in fetuses between 6-12 hours.

Ezogabine has a novel mechanism of action that involves opening of neuronal Kv7.2-7.5 (formerly KCNQ2-5) voltage activated potassium channels. These channels (primarily Kv7.2/7.3) enable generation of the M-current, a sub-threshold potassium current that serves to stabilize the membrane potential and control neuronal excitability. In addition to acting on potassium ion channels, retigabine also affects GABA neurotransmission in the GABA-A receptor, which is a key inhibitory receptor in the central nervous system and is implicated in epilepsy. Malfunctioning of the GABA-A receptor leads to hyperexcitability in the brain, which causes seizures, making this receptor an important target for antiepileptic therapeutics. Apart from increasing the concentration of GABA in the brain (by either enhancing GABA synthesis or blocking GABA metabolism), retigabine allosterically potentiates GABA-induced current in rat cortical neurons in a concentration-dependent manner. Numerous studies have demonstrated that retigabine is effective in a broad spectrum of in vivo epilepsy and seizure models.|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 stabilizes cellular excitability. The MoA of RTG/EZG increases the number of KCNQ channels that are open at rest and also primes the cell to retort with a larger, more rapid, and more prolonged response to membrane depolarization or increased neuronal excitability. In this way, RTG/EZG amplifies this natural inhibitory force in the brain, acting like a brake to prevent the high levels of neuronal action potential burst firing (epileptiform activity) that may accompany sustained depolarizations associated with the initiation and propagation of seizures. This action to restore physiologic levels of neuronal activity is thought to underlie the efficacy of RTG/EZG as an anticonvulsant in a broad spectrum of preclinical seizure models and in placebo-controlled trials in patients with partial epilepsy. ...|The mechanism by which ezogabine exerts its therapeutic effects has not been fully elucidated. In vitro studies indicate that ezogabine enhances transmembrane potassium currents mediated by the KCNQ (Kv7.2 to 7.5) family of ion channels. By activating KCNQ channels, ezogabine is thought to stabilize the resting membrane potential and reduce brain excitability. In vitro studies suggest that ezogabine may also exert therapeutic effects through augmentation of GABA-mediated currents.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|There is no specific antidote for overdose with Potiga. In the event of overdose, standard medical practice for the management of any overdose should be used. An adequate airway, oxygenation, and ventilation should be ensured; monitoring of cardiac rhythm and vital sign measurement is recommended.

/HUMAN EXPOSURE STUDIES/ A human abuse potential study was conducted in recreational sedative-hypnotic abusers (n = 36) in which single oral doses of ezogabine (300 mg (n = 33), 600 mg [n = 34], 900 mg (n =6)), the sedative-hypnotic alprazolam (1.5 mg and 3.0 mg), and placebo were administered. Euphoria-type subjective responses to the 300-mg and 600-mg doses of ezogabine were statistically different from placebo but statistically indistinguishable from those produced by either dose of alprazolam. Adverse events reported following administration of single oral doses of 300 mg, 600 mg, and 900 mg ezogabine given without titration included euphoric mood (18%, 21%, and 33%, respectively; 8% from placebo), hallucination (0%, 0%, and 17%, respectively; 0% from placebo) and somnolence (18%, 15%, and 67%, respectively; 15% from placebo).|/HUMAN EXPOSURE STUDIES/ In an abuse potential study, cardiac arrhythmia (asystole or ventricular tachycardia) occurred in 2 volunteers within 3 hours of receiving a single 900-mg dose of Potiga. The arrhythmias spontaneously resolved and both volunteers recovered without sequelae.|/SIGNS AND SYMPTOMS/ There is limited experience of overdose with Potiga. Total daily doses of Potiga over 2,500 mg were reported during clinical trials. In addition to adverse reactions seen at therapeutic doses, symptoms reported with Potiga overdose included agitation, aggressive behavior, and irritability. There were no reported sequelae.|/GENOTOXICITY/ Ezogabine was positive in the in vitro chromosomal aberration assay in human lymphocytes.

D 20443

Ezogabine|Potiga|2779|Schedule V - Substances in the DEA Schedule V have a low potential for abuse relative to substances listed in Schedule IV and consist primarily of preparations containing limited quantities of certain narcotics.|No

Trobalt contains the active substance retigabine. ... The product is formulated as immediate-release film-coated tablets in the strengths 50 mg, 100 mg, 200 mg, 300 mg and 400 mg.|Table: Ezogabine Preparations [Table#8160]

HPLC/MS/MS determination in plasma.|LC/MS/MS determination of the active, N-acetyl metabolite in plasma.

Human drugs -> Trobalt -> EMA Drug Category|Antiepileptics -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human drugs -> Rare disease (orphan)|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients