Dosing & Uses
Dosage Forms & Strengths
tablet: Schedule V
- 50mg
- 200mg
- 300mg
- 400mg
Partial Onset Seizures
Indicated as adjunctive therapy in partial onset seizures uncontrolled by current medications and for whom the benefits outweigh the risk of retinal abnormalities and potential decline in visual acuity
Initial: 100 mg PO q8hr; may increase dose at weekly intervals, not to exceed dosage increase of 150 mg/day/week
Optimize effective dosage between 200 mg 3 times daily (600 mg per day) to 400 mg 3 times daily (1,200 mg per day)
In controlled clinical trials, 400 mg q8hr (1,200 mg/day) showed limited improvement compared to 300 mg q8hr (900 mg/day) with an increase in adverse reactions and discontinuations
Renal Impairment
Mild renal impairment (CrCl 50-80 mL/min): AUC increased by 30%
Moderate/end-stage renal impairment
- CrCl <50 mL/min
- Initial: 50 mg PO q8hr; may increase at weekly intervals in increments of <150 mg/day
- Maximum dose: Not to exceed 200 mg PO q8hr
- Hemodialysis: Immediately following dialysis, administer a single supplemental dose; if breakthrough seizures occur toward end of hemodialysis, consider additional supplemental dose at the start of subsequent dialysis sessions
Hepatic impairment
Mild hepatic impairment (Child-Pugh 5-6): AUC not affected
Moderate impairment
- (Child-Pugh 7-9): AUC increased ~50%; decrease initial and maintenance doses by 50%
- Initial: 50 mg PO q8hr; may increase dose at weekly intervals, not to exceed dosage increase of 50 mg/day/week
- Maximum dose: Not to exceed 250 mg PO q8hr
Severe impairment
- (Child-Pugh >9): AUC increased ~100%; decrease initial and maintenance doses by 50%
- Initial: 50 mg PO q8hr; may increase dose at weekly intervals, not to exceed dosage increase of 50 mg/day/week
- Maximum dose: Not to exceed 200 mg PO q8hr
Dosing Considerations
May cause retinal abnormalities with long-term use; therefore, treatment should be discontinued if patients fail to show substantial clinical benefit after adequate titration
Testing of visual function should be done at baseline and every 6 months during therapy
If retinal pigmentary abnormalities or vision changes are detected, discontinue unless no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss
<18 years: Safety and efficacy not established
Partial Onset Seizures
Initial: 50 mg PO q8hr; may increase dose at weekly intervals, not to exceed dosage increase of 50 mg/day/week
Maximum dose: Not to exceed 250 mg PO q8hr
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
In 3 controlled clinical studies, 25% of patients receiving ezogabine (199/813) and 11% of patients receiving placebo (45/427) discontinued treatment because of treatment-emergent adverse reactions
>10%
Dizziness (23%)
Somnolence (22%)
Fatigue (15%)
1-10%
Confusion (9%)
Vertigo (8%)
Tremor (8%)
Nausea (7%)
Abnormal coordination (7%)
Diplopia (7%)
Attention disturbance (6%)
Memory impairment (6%)
Asthenia (5%)
Blurred vision (5%)
Gait disturbance (4%)
Aphasia (4%)
Dysarthria (4%)
Balance disorder (4%)
Anxiety (3%)
Paresthesia (3%)
Infections (3%)
Weight gain (3%)
Constipation (3%)
Disorientation (2%)
Dyspepsia (2%)
Dysuria (2%)
Urinary retention/hesitation (2%)
Hematuria (2%)
Chromaturia (2%)
Hallucinations (2%)
Amnesia (2%)
Dysphasia (2%)
<1%
Psychotic disorder
Postmarketing Reports
Acquired vitelliform lesions
Warnings
Black Box Warnings
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; unknown if ezogabine caused this vision loss
Rate of progression of retinal abnormalities and their reversibility are unknown; about 33% of patients who had eye examinations performed after 4 yr of treatment were found to have retinal pigmentary abnormalities; an earlier onset cannot be ruled out
Discontinue if patient fails to show substantial clinical benefit after adequate titration
All patients should have baseline and periodic (every 6 months) systematic visual monitoring by an ophthalmic professional; testing should include visual acuity and dilated fundus photography
If retinal pigmentary abnormalities or vision changes are detected, discontinue ezogabine unless no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss
Contraindications
Hypersensitivity
Cautions
Slight and transient QT-prolongation observed; caution when administered with concomitant drugs that prolong QT interval, congenital long QT syndrome, heart failure, ventricular hypertrophy, hypokalemia, or hypomagnesemia
Can cause retinal abnormalities (see Black Box Warnings)
Caution with existing conditions that may cause urinary retention; monitor for urologic symptoms
Monitor for confusional state, psychotic symptoms, or hallucinations
Monitor for dizziness and somnolence
Monitor for suicidal thoughts or behavior
Phenytoin or carbamazepine may decrease ezogabine serum levels
Macular abnormalities characterized as vitelliform lesions observed; lesions may also be seen in macular degenerative and dystrophic disorders
N-acetyl metabolite of ezogabine (NAMR) may inhibit renal clearance of digoxin, a P-gp substrate; monitor digoxin levels
Skin discoloration
- Can cause skin discoloration that is generally described as blue, but has also been described as grey-blue or brown
- Discoloration occurs predominantly on or around the lips or in the nail beds of the fingers or toes, but more widespread involvement of the face and legs has also been reported
- Discoloration of the palate, sclera, and conjunctiva has also been reported
- ~10% of patients in long-term clinical trials developed skin discoloration, generally after ≥2 yr of treatment and at higher doses (≥900 mg/day)
Pregnancy & Lactation
Pregnancy Category: C; based on animal data, may cause fetal harm (developmental toxicity)
North American Antiepileptic Drug (NAAED) Pregnancy Registry: 1-888-233-2334
Lactation: Unknown whether distributed in human breast milk; excreted in milk of lactating rats
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Antiseizure agent; neuronal potassium channel opener
Stabilizes neuronal KCNQ (Kv7) channels in the open position, increasing the stabilizing membrane current and preventing bursts of action potentials during the sustained depolarizations associated with seizures
May also augment gamma-aminobutyric acid (GABA) mediated neurotransmission
Pharmacokinetics
Bioavailability: ~60%
Peak Plasma Time: 0.5-2 hr (variable and may be lower in fasted stated)
Protein Bound: 80% (when concentration ranges between 0.1-2 mcg/mL); 45% (NAMR active metabolite)
Vd: 2-3 L/kg following IV
Metabolized by N-glucuronidation (primarily (UGT1A4) and N-acetylation (primarily NAT2)
Not a substrate, inducer, or inhibitor of CYP3A4 isoenzymes
Ezogabine is neither a substrate nor an inhibitor of the P-glycoprotein transporter and would not be expected to interact with drugs which are either P-glycoprotein inhibitors or substrates
Metabolites: Primary metabolites of ezogabine were the N2- and N4-glucuronides of ezogabine, the N-acetyl metabolite of ezogabine (NAMR) and the N2- and N4-glucuronides of NAMR
NAMR is not expected to have any impact on the overall pharmacological activity/safety of administered ezogabine
NAMR may inhibit the renal tubular secretion of digoxin, resulting in increased serum levels
Elimination
- Half-life: 7-11 hr (similar for both parent drug and active metabolite)
- Total body clearance: 0.4-0.6 L/hr/kg
- Excretion: feces (14%), urine (85%)
Administration
Oral Administration
Take orally in 3 equally divided doses with or without food
Swallow tablet whole, do not chew, split, or crush
When discontinuing, reduce dose gradually over at least 3 weeks, unless safety concerns require abrupt withdrawal
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