ezogabine (Potiga)

Dosing and uses of Potiga (ezogabine)

• Adult
• Pediatric
• Geriatric

 

Adult dosage forms and 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

 

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

 

Pediatric dosage forms and strengths

<18 years: Safety and efficacy not established

 

Geriatric dosage forms and strengths

 

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

 

Potiga (ezogabine) adverse (side) 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 and 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 of Potiga (ezogabine)

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%)