Ezogabine

Keep container tightly closed in a dry and well-ventilated place.

Store at 25 °C (77 dg F); excursions permitted between 15 deg -30 °C (59 deg -86 °F).

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: 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.

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.

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).

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.

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.

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.

/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.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a one-year neonatal mouse study of ezogabine (2 single-dose oral administrations of up to 96 mg/kg on postnatal days 8 and 15), a dose-related increase in the frequency of lung neoplasms (bronchioalveolar carcinoma and/or adenoma) was observed in treated males. No evidence of carcinogenicity was observed in rats following oral administration of ezogabine (oral gavage doses of up to 50 mg/kg/day) for 2 years. Plasma exposure (AUC) to ezogabine at the highest doses tested was less than that in humans at the maximum recommended human dose (MRHD) of 1,200 mg per day.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Ezogabine had no effect on fertility, general reproductive performance, or early embryonic development when administered to male and female rats at doses of up to 46.4 mg/kg/day (associated with a plasma ezogabine exposure (AUC) less than that in humans at the maximum recommended human dose (MRHD)) prior to and during mating, and continuing in females through gestation day 7.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Administration of ezogabine (oral doses of up to 61.9 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased pre- and postnatal mortality, decreased body weight gain, and delayed reflex development in the offspring. The no-effect dose for pre- and postnatal developmental effects in rats (17.8 mg/kg/day) was associated with maternal plasma exposures to ezogabine and the N-acetyl metabolite of ezogabine (NAMR) less than those in humans at the maximum recommended human dose (MRHD).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Treatment of pregnant rabbits with ezogabine (oral doses of up to 60 mg/kg/day) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal skeletal variations. The no-effect dose for embryo-fetal toxicity in rabbits (12 mg/kg/day) was associated with maternal plasma exposures to ezogabine and the N-acetyl metabolite of ezogabine (NAMR) less than those in humans at the maximum recommended human dose (MRHD).

For more Non-Human Toxicity Excerpts (Complete) data for Ezogabine (7 total), please visit the HSDB record page.

/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.

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.

Ezogabine is a Schedule V controlled substance.

Schedule V Controlled Substance: (A) The drug or other substance has a low potential for abuse relative to the drugs or other substances in schedule IV. (B) The drug or other substance has a currently accepted medical use in treatment in the United States. (C) Abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in schedule IV.

Anticonvulsants; Membrane Transport Modulators

THERAPEUTIC CATEGORY: Anticonvulsant

MEDICATION

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#8148]