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EZOGABINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ezogabine, an antiepileptic agent, is a potassium channel opener.

Specific Substances

    1) Retigabine
    2) Ethyl 2-amino-4[(p-fluorobenzyl)amino]carbanilate
    3) D-23129
    4) GKE-841
    5) WAY-143841
    6) CAS 150812-12-7
    1.2.1) MOLECULAR FORMULA
    1) C16-H18-F-N3-O2 (Prod Info POTIGA(TM) oral tablets, 2011)

Available Forms Sources

    A) FORMS
    1) Ezogabine is available as 50 mg, 200 mg, 300 mg, and 400 mg film-coated tablets (Prod Info POTIGA(TM) oral tablets, 2011).
    B) USES
    1) Ezogabine is used as adjunctive therapy for partial-onset seizures in patients 18-years-old and older (Prod Info POTIGA(TM) oral tablets, 2011).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Ezogabine is used as adjunctive therapy for partial-onset seizures in patients 18-years-old and older.
    B) PHARMACOLOGY: Ezogabine is an anticonvulsant that enhances transmembrane potassium currents mediated by the KCNQ (Kv7.2 to 7.5) family of ion channels. By activating and opening these KCNQ channels, ezogabine helps stabilize the resting membrane potential and reduce brain excitability. In vitro studies also suggest that ezogabine augments GABA-mediated currents.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Dizziness, somnolence, fatigue, confusion, vertigo, tremor, abnormal coordination, diplopia, memory impairment, asthenia, blurred vision, gait disturbance, aphasia, dysarthria, and balance disorder.
    2) INFREQUENT: Other adverse effects that have occurred less frequently include: QT interval prolongation, dysuria, urinary retention, nausea, constipation, hallucinations, and anxiety.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Agitation, aggressiveness, and irritability were reported during clinical trials with total daily doses greater than 2500 mg.
    2) SEVERE TOXICITY: Cardiac dysrhythmias (asystole or ventricular tachycardia) occurred in 2 volunteers within 3 hours of ingesting a single 900-mg ezogabine dose. Both individuals recovered, without sequelae, following spontaneous resolution of the dysrhythmias. Ezogabine prolongs the QT interval, Torsades de Pointes is possible but has not been reported.
    0.2.20) REPRODUCTIVE
    A) Ezogabine is classified as FDA pregnancy category C.
    B) In animal studies, developmental toxicity, including fetal skeletal variations and decreased fetal body weights, were reported with maternal administration of ezogabine.

Laboratory Monitoring

    A) Routine laboratory studies are not likely to be necessary.
    B) Monitor neurologic status after significant overdose
    C) Obtain a baseline ECG, and institute continuous cardiac monitoring following a significant overdose.
    D) Monitor urine output for evidence of urinary retention.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Most patients require only supportive care. Control agitation and confusion with benzodiazepines .
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat agitation with benzodiazepines. Therapeutic doses of ezogabine may cause prolongation of the QT interval. Concomitant use of ezogabine and other drugs that prolong the QT interval may increase the risk of torsade de pointes. Treat torsade de pointes with IV magnesium sulfate, and correct electrolyte abnormalities, overdrive pacing may be necessary. Treat ventricular dysrhythmias using standard ACLS protocols.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal after a recent potentially toxic ingestion of ezogabine, if the patient is awake and able to maintain their airway or if the airway is protected.
    D) AIRWAY MANAGEMENT
    1) Endotracheal intubation and mechanical ventilation may rarely be required in patients with significant CNS depression or ventricular dysrhythmias.
    E) ANTIDOTE
    1) None.
    F) TORSADES DE POINTES
    1) Therapeutic doses of ezogabine may cause prolongation of the QT interval. Concomitant use of ezogabine and other drugs that prolong the QT interval may increase the risk of torsade de pointes.
    2) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium, and/or atrial overdrive pacing. Correct electrolyte abnormalities (hypomagnesemia, hypokalemia, hypocalcemia). MAGNESIUM SULFATE/DOSE: ADULT: 1 to 2 g IV (mixed in 50 to 100 mL D5W) infused over 5 min, repeat 2 g bolus and begin infusion of 0.5 to 1 g/hr if dysrhythmias recur. CHILD: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 min. OVERDRIVE PACING: Begin at 130 to 150 beats/min, decrease as tolerated. Rates of 100 to 120 beats/min may terminate torsades. Avoid class Ia (quinidine, disopyramide, procainamide), class Ic (flecainide, encainide, propafenone) and most class III antidysrhythmics (N-acetylprocainamide, sotalol).
    G) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic children (other than mild drowsiness) with a minor (50 mg or less) inadvertent ingestion may be monitored at home with appropriate adult supervision.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.
    3) ADMISSION CRITERIA: Patients who remain symptomatic or have persistent ECG abnormalities despite adequate treatment should be admitted. Patients with dysrhythmias should be admitted to an ICU setting.
    4) CONSULT CRITERIA: Contact a Poison Center or a medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    I) PITFALLS
    1) When managing a suspected ezogabine overdose, the possibility of coingestion of other agents should be considered.
    J) PHARMACOKINETICS
    1) Oral bioavailability is 60%. Plasma protein binding is approximately 80%. Volume of distribution is 2 to 3 L/kg. Extensively metabolized in liver via glucuronidation and acetylation; NAMR is the active metabolite. Approximately 85% of a dose is excreted renally, with 36% recovered as unchanged drug. Elimination half-life is 7 to 11 hours; half-life may be increased by approximately 30% in elderly patients (greater than 65 years of age).
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause QT interval prolongation.

Range Of Toxicity

    A) TOXICITY: During clinical trials, total daily doses greater than 2500 mg resulted in agitation, aggressiveness, and irritability. Cardiac dysrhythmias (asystole or ventricular tachycardia) were reported in 2 volunteers within 3 hours of ingesting a single 900-mg dose of ezogabine. Both individuals recovered, without sequelae, following spontaneous resolution of the dysrhythmias.
    B) THERAPEUTIC DOSE: ADULT: 600 to 1200 mg orally in 3 equally divided doses. ELDERLY PATIENTS: 150 to 750 mg orally in 3 equally divided doses. PEDIATRIC: The safety and efficacy of ezogabine in patients under 18 years of age have not been studied.

Clinical Effects

Summary Of Exposure

    A) USES: Ezogabine is used as adjunctive therapy for partial-onset seizures in patients 18-years-old and older.
    B) PHARMACOLOGY: Ezogabine is an anticonvulsant that enhances transmembrane potassium currents mediated by the KCNQ (Kv7.2 to 7.5) family of ion channels. By activating and opening these KCNQ channels, ezogabine helps stabilize the resting membrane potential and reduce brain excitability. In vitro studies also suggest that ezogabine augments GABA-mediated currents.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Dizziness, somnolence, fatigue, confusion, vertigo, tremor, abnormal coordination, diplopia, memory impairment, asthenia, blurred vision, gait disturbance, aphasia, dysarthria, and balance disorder.
    2) INFREQUENT: Other adverse effects that have occurred less frequently include: QT interval prolongation, dysuria, urinary retention, nausea, constipation, hallucinations, and anxiety.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Agitation, aggressiveness, and irritability were reported during clinical trials with total daily doses greater than 2500 mg.
    2) SEVERE TOXICITY: Cardiac dysrhythmias (asystole or ventricular tachycardia) occurred in 2 volunteers within 3 hours of ingesting a single 900-mg ezogabine dose. Both individuals recovered, without sequelae, following spontaneous resolution of the dysrhythmias. Ezogabine prolongs the QT interval, Torsades de Pointes is possible but has not been reported.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) DIPLOPIA: In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, diplopia was reported in 8%, 6%, and 7% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with 2% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    2) BLURRED VISION: In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, blurred vision was reported in 2%, 4%, and 10% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with 2% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011)

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) A mean 7.7-msec prolongation of the QT interval was noted within 3 hours of administration of ezogabine (titrated to 400 mg 3 times daily) in healthy subjects (Prod Info POTIGA(TM) oral tablets, 2011).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) Cardiac dysrhythmias (asystole or ventricular tachycardia) were reported in 2 volunteers within 3 hours of ingesting a single 900-mg dose of ezogabine. Both individuals recovered, without sequelae, following spontaneous resolution of the dysrhythmias (Prod Info POTIGA(TM) oral tablets, 2011).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, dizziness was reported in 15%, 23%, and 32% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with 9% of patients who received placebo (n=427). Most cases were mild to moderate, were reported during initial titration, and diminished with continued use of ezogabine (Prod Info POTIGA(TM) oral tablets, 2011).
    B) DROWSY
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, somnolence was reported in 15%, 25%, and 27% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with 12% of patients who received placebo (n=427). Most cases were mild to moderate, were reported during initial titration, and diminished with continued use of ezogabine (Prod Info POTIGA(TM) oral tablets, 2011).
    C) FEELING AGITATED
    1) WITH POISONING/EXPOSURE
    a) Agitation, aggressiveness, and irritability were reported in patients during clinical trials following ezogabine ingestions of total daily doses greater than 2500 mg (Prod Info POTIGA(TM) oral tablets, 2011).
    D) MEMORY IMPAIRMENT
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, memory impairment was reported in 3%, 6%, and 9% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with 3% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    E) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, asthenia was reported in 4%, 6%, and 4% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with 2% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    F) TREMOR
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, tremor was reported in 3%, 10%, and 12% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with 3% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    G) VERTIGO
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, vertigo was reported in 8%, 8%, and 9% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with 2% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    H) INCOORDINATION
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, abnormal coordination was reported in 5%, 5%, and 12% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with 3% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    I) DISTURBANCE OF ATTENTION
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, disturbance in attention was reported in 6%, 6%, and 7% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with less than 1% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    J) ABNORMAL GAIT
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, gait disturbance was reported in 2%, 5%, and 6% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with 1% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    K) APHASIA
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, aphasia was reported in 1%, 3%, and 7% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with less than 1% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    L) DYSARTHRIA
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, dysarthria was reported in 4%, 2%, and 8% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with less than 1% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    M) PROBLEM WITH BALANCE
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, balance disorder was reported in 3%, 3%, and 5% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with less than 1% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    N) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) Confusion was a dose-related adverse effect which generally occurred within the first 8 weeks of therapy during controlled- and open-label trials. In most patients, symptoms resolved within 7 days of discontinuation of ezogabine. In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, confusion was reported in 4%, 8%, and 16% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with 3% of patients who received placebo (n=427). Confusional state also lead to the discontinuation of therapy in 4% of patients who received ezogabine compared with less than 1% in placebo (Prod Info POTIGA(TM) oral tablets, 2011).
    O) FATIGUE
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, fatigue was reported in 16%, 15%, and 13% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with 6% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    P) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, paresthesia was reported in 3%, 2%, and 5% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with 2% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, nausea was reported in 6%, 6%, and 9% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with 5% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, constipation was reported in 1%, 4%, and 5% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with 1% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) DYSURIA
    1) WITH THERAPEUTIC USE
    a) Dysuria, and urinary retention and hesitation, usually reported within the first 6 months of treatment, have been associated with ezogabine therapy. Some patients have required catheterization and some have also required continued intermittent catheterization following discontinuation of therapy (Prod Info POTIGA(TM) oral tablets, 2011).
    b) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, dysuria was reported in 1%, 2%, and 4% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with less than 1% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    c) Dysuria was reported in 2.3% of patients who received ezogabine compared with 0.7% of patients who received placebo during placebo-controlled epilepsy trials (Prod Info POTIGA(TM) oral tablets, 2011).
    B) DELAY WHEN STARTING TO PASS URINE
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, urinary hesitation was reported in 2%, 1%, and 4% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with less than 1% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    b) Urinary hesitation was reported in 2.2% of patients who received ezogabine compared with 0.9% of patients who received placebo during placebo-controlled epilepsy trials (Prod Info POTIGA(TM) oral tablets, 2011).
    C) BLOOD IN URINE
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, hematuria was reported in 2%, 1%, and 2% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with less than 1% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    D) URINE COLOR ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, chromaturia was reported in less than 1%, 2%, and 3% of patients who received ezogabine 600 mg/day (n=281), 900 mg/day (n=273), and 1200 mg/day (n=259), respectively, compared with less than 1% of patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    E) RETENTION OF URINE
    1) WITH THERAPEUTIC USE
    a) Urinary retention, usually presenting in the first 6 months, was reported in approximately 2% (29 of 1365) of epilepsy patients who received ezogabine during open-label and placebo-controlled clinical trials. Catheterization was required in 14% (4 of 29) of these patients, with postvoiding residuals up to 1500 mL. All 4 patients were able to void spontaneously following drug discontinuation; however, 1 patient required intermittent self-catheterization. Retention led to hydronephrosis in 2 ezogabine-treated patients, but resolved with drug withdrawal (Prod Info POTIGA(TM) oral tablets, 2011).
    b) In 3 randomized, double-blind, controlled clinical trials of adult patients with partial-onset seizures, urinary retention was reported in less than 2% of patients who received ezogabine 600 to 1200 mg/day (n=813), and occurred more frequently than in patients who received placebo (n=427) (Prod Info POTIGA(TM) oral tablets, 2011).
    c) Urinary retention was reported in 0.9% of patients who received ezogabine compared with 0.5% of patients who received placebo during placebo-controlled epilepsy trials (Prod Info POTIGA(TM) oral tablets, 2011).

Reproductive

    3.20.1) SUMMARY
    A) Ezogabine is classified as FDA pregnancy category C.
    B) In animal studies, developmental toxicity, including fetal skeletal variations and decreased fetal body weights, were reported with maternal administration of ezogabine.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) In animal studies, developmental toxicity was reported in the offspring of pregnant rats and rabbits administered ezogabine doses similar to or below the maternal plasma exposures expected in humans at the maximum recommended human dose (MRHD) of 1200 mg/day. Fetal skeletal variations were reported with ezogabine doses up to 46 mg/kg/day in pregnant rats. In rabbits, ezogabine doses up to 60 mg/kg/day throughout organogenesis resulted in increased fetal skeletal variations and decreased fetal body weights. The no-effect dose for embryo-fetal toxicity in rats and rabbits was 21 and 12 mg/kg/day, respectively (less than the AUC of ezogabine and its metabolite in humans at the MRHD). Delayed reflex development in the offspring was reported in rats administered ezogabine oral doses up to 61.9 mg/kg/day throughout pregnancy and lactation. The no-effect dose was 17.8 mg/kg/day (less than the AUC of ezogabine and its metabolite in humans at the MRHD) (Prod Info POTIGA(TM) oral tablets, 2011).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Ezogabine is classified as FDA pregnancy category C (Prod Info POTIGA(TM) oral tablets, 2011).
    2) To provide data regarding the effects of in utero ezogabine exposure, it is recommended that pregnant patients receiving ezogabine therapy enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334. Enrollment must be completed by the patient. Further information regarding this pregnancy registry may be found at www.aedpregnancyregistry.org (Prod Info POTIGA(TM) oral tablets, 2011).
    B) ANIMAL STUDIES
    1) RATS: Increased prenatal and postnatal mortality and decreased body weight gain were reported in rats administered ezogabine oral doses up to 61.9 mg/kg/day throughout pregnancy and lactation. The no-effect dose was 17.8 mg/kg/day (less than the AUC of ezogabine and its metabolite in humans at the MRHD) (Prod Info POTIGA(TM) oral tablets, 2011)
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) Lactation studies with ezogabine have not been conducted in humans. It is not known whether ezogabine is excreted in human breast milk (Prod Info POTIGA(TM) oral tablets, 2011).
    B) ANIMAL STUDIES
    1) RATS: Animal studies have shown that ezogabine and/or its metabolites are excreted in the milk of lactating rats (Prod Info POTIGA(TM) oral tablets, 2011).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT: There was no effect on fertility, general reproductive performance, or early embryonic development when ezogabine was administered to male and female rats prior to and during mating, and continuing in females through gestation day 7, at doses up to 46.4 mg/kg/day (plasma ezogabine exposure (AUC) less than the maximum recommended human dose) (Prod Info POTIGA(TM) oral tablets, 2011).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LUNG NEOPLASM
    1) MICE: Following a year-long study, a dose-related increase in the frequency of lung neoplasms (bronchioalveolar carcinoma and/or adenoma) in neonatal male mice was observed. The mice were given ezogabine as 2 single-doses up to 96 mg/kg, administered orally on postnatal days 8 and 15 (Prod Info POTIGA(TM) oral tablets, 2011).
    B) LACK OF EFFECT
    1) RATS: Following oral gavage of ezogabine at doses up to 50 mg/kg/day for 2 years, there appeared to be no evidence of carcinogenicity (Prod Info POTIGA(TM) oral tablets, 2011).

Genotoxicity

    A) Ezogabine was negative for mutagenicity in the in vitro Ames assay, the in vitro Chinese hamster ovary Hprt gene mutation assay, and the in vivo mouse micronucleus assay; however, ezogabine was positive in the in vitro chromosomal aberration assay in human lymphocytes. Ezogabine's major metabolite, NAMR, was negative in the in vitro Ames assay, but was positive in the in vitro chromosomal aberration assay in Chinese hamster ovary cells (Prod Info POTIGA(TM) oral tablets, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Routine laboratory studies are not likely to be necessary.
    B) Monitor neurologic status after significant overdose
    C) Obtain a baseline ECG, and institute continuous cardiac monitoring following a significant overdose.
    D) Monitor urine output for evidence of urinary retention.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    4.1.2) SERUM/BLOOD
    A) Routine laboratory studies are not likely to be necessary.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    4.1.3) URINE
    A) Monitor urine output for evidence of urinary retention.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain a baseline ECG, and institute continuous cardiac monitoring following a significant overdose. QT prolongation develops at therapeutic doses and dysrhythmias have been reported after overdose.
    2) MONITORING
    a) Monitor neurologic status after significant overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic or have persistent ECG changes despite adequate treatment should be admitted. Patients with dysrhythmias should be admitted to an ICU setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic children (other than mild drowsiness) with a minor (50 mg or less) inadvertent ingestion may be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.

Monitoring

    A) Routine laboratory studies are not likely to be necessary.
    B) Monitor neurologic status after significant overdose
    C) Obtain a baseline ECG, and institute continuous cardiac monitoring following a significant overdose.
    D) Monitor urine output for evidence of urinary retention.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. Control agitation and confusion with benzodiazepines . There is no specific antidote for ezogabine.
    B) MONITORING OF PATIENT
    1) Routine laboratory studies are not likely to be necessary.
    2) Monitor neurologic statuss.
    3) Obtain an ECG, and institute continuous cardiac monitoring..
    4) Monitor urine output for evidence of urinary retention.
    5) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) TORSADES DE POINTES
    1) Therapeutic doses of ezogabine may cause prolongation of the QT interval. Concomitant use of ezogabine and other drugs that prolong the QT interval may increase the risk of torsade de pointes.
    2) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    3) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    4) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    5) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    6) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    7) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    8) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.
    D) RETENTION OF URINE
    1) Urinary retention may require placement of a catheter.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.

Range Of Toxicity

Summary

    A) TOXICITY: During clinical trials, total daily doses greater than 2500 mg resulted in agitation, aggressiveness, and irritability. Cardiac dysrhythmias (asystole or ventricular tachycardia) were reported in 2 volunteers within 3 hours of ingesting a single 900-mg dose of ezogabine. Both individuals recovered, without sequelae, following spontaneous resolution of the dysrhythmias.
    B) THERAPEUTIC DOSE: ADULT: 600 to 1200 mg orally in 3 equally divided doses. ELDERLY PATIENTS: 150 to 750 mg orally in 3 equally divided doses. PEDIATRIC: The safety and efficacy of ezogabine in patients under 18 years of age have not been studied.

Therapeutic Dose

    7.2.1) ADULT
    A) For adults 18 years and older, the recommended total daily dose of ezogabine as adjunctive therapy for the treatment of partial seizures is 600 to 1200 mg orally in 3 equally divided doses. It is recommended that therapy be initiated at 100 mg 3 times daily followed by weekly titration in increments not to exceed 150 mg/day (50 mg 3 times daily). Doses above 1200 mg/day have not been studied (Prod Info POTIGA(TM) oral tablets, 2011).
    B) ELDERLY: In geriatric patients (age over 65 years), the recommended initial dosage is 50 mg orally 3 times daily; titration should not exceed weekly increases of 50 mg 3 times daily, to a maximum recommended maintenance dose of 250 mg 3 times daily (750 mg/day) (Prod Info POTIGA(TM) oral tablets, 2011)
    7.2.2) PEDIATRIC
    A) Safety and efficacy in pediatric patients have not been established (Prod Info POTIGA(TM) oral tablets, 2011).

Maximum Tolerated Exposure

    A) During clinical trials, total daily doses greater than 2500 mg resulted in agitation, aggressiveness, and irritability (Prod Info POTIGA(TM) oral tablets, 2011).
    B) Cardiac dysrhythmias (asystole or ventricular tachycardia) occurred in 2 volunteers within 3 hours of ingesting a single 900-mg ezogabine dose. Both individuals recovered, without sequelae, following spontaneous resolution of the dysrhythmias (Prod Info POTIGA(TM) oral tablets, 2011).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Ezogabine is an anticonvulsant that enhances transmembrane potassium currents mediated by the KCNQ (Kv7.2 to 7.5) family of ion channels. By activating and opening these KCNQ channels, ezogabine helps stabilize the resting membrane potential and reduce brain excitability. In vitro studies also suggest that ezogabine augments GABA-mediated currents (Prod Info POTIGA(TM) oral tablets, 2011).

Physicochemical

Physical Characteristics

    A) Ezogabine is a white to slightly colored, odorless, tasteless, crystalline powder. At a pH above 4 (at room temperature), ezogabine is practically insoluble in aqueous media, but has greater solubility in polar organic solvents. At gastric pH, ezogabine is sparingly soluble in water (approximately 16 g/L) (Prod Info POTIGA(TM) oral tablets, 2011).

Molecular Weight

    A) 303.3 (Prod Info POTIGA(TM) oral tablets, 2011)

References

General Bibliography

    1) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    2) Charlton NP , Lawrence DT , Brady WJ , et al: Termination of drug-induced torsades de pointes with overdrive pacing. Am J Emerg Med 2010; 28(1):95-102.
    3) Drew BJ, Ackerman MJ, Funk M, et al: Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2010; 55(9):934-947.
    4) Keren A, Tzivoni D, & Gavish D: Etiology, warning signs and therapy of torsade de pointes: a study of 10 patients. Circulation 1981; 64:1167-1174.
    5) Khan IA & Gowda RM: Novel therapeutics for treatment of long-QT syndrome and torsade de pointes. Int J Cardiol 2004; 95(1):1-6.
    6) Link MS, Berkow LC, Kudenchuk PJ, et al: Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S444-S464.
    7) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    8) Perticone F, Ceravolo R, & Cuccurullo O: Prolonged magnesium sulfate infusion in the treatment of ventricular tachycardia in acquired long QT syndrome. Clin Drug Inverst 1997; 13:229-236.
    9) Product Information: Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, isoproterenol HCl intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection. Hospira, Inc. (per FDA), Lake Forest, IL, 2013.
    10) Product Information: POTIGA(TM) oral tablets, ezogabine oral tablets. GlaxoSMithKline (per FDA), Research Triangle Park, NC, 2011.
    11) Product Information: magnesium sulfate heptahydrate IV, IM injection, solution, magnesium sulfate heptahydrate IV, IM injection, solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2009.
    12) Smith WM & Gallagher JJ: "Les torsades de pointes": an unusual ventricular arrhythmia. Ann Intern Med 1980; 93:578-584.