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Ezogabine

Pronunciation

(e ZOG a been)

Index Terms

  • D-23129
  • EZG
  • Retigabine
  • RTG

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Potiga: 50 mg [contains fd&c blue #2 (indigotine)]

Potiga: 200 mg

Potiga: 300 mg, 400 mg [contains fd&c blue #2 (indigotine)]

Brand Names: U.S.

  • Potiga

Pharmacologic Category

  • Anticonvulsant, Neuronal Potassium Channel Opener

Pharmacology

Ezogabine binds the KCNQ (Kv7.2-7.5) voltage-gated potassium channels, thereby stabilizing the channels in the open formation and enhancing the M-current. As a result, neuronal excitability is regulated and epileptiform activity is suppressed. In addition, ezogabine may also exert therapeutic effects through augmentation of GABA-mediated currents.

Absorption

Rapid

Distribution

Vdss: 2 to 3 L/kg

Metabolism

Glucuronidation via UGT1A4, UGT1A1, UGT1A3, and UGT1A9 and acetylation via NAT2 to an N-acetyl active metabolite (NAMR) and other inactive metabolites (eg, N-glucuronides, N-glucoside)

Excretion

Urine (~85%, 36% of total dose as unchanged drug, 18% of total dose as NAMR); feces (~14%, 3% of total dose as unchanged drug)

Time to Peak

Plasma: 0.5 to 2 hours; delayed by 0.75 hours when administered with high-fat food

Half-Life Elimination

Ezogabine and NAMR: 7 to 11 hours; increased by ~30% in elderly patients

Protein Binding

Ezogabine: ~80%; N-acetyl active metabolite (NAMR): ~45%

Special Populations: Renal Function Impairment

The AUC was increased by ~30% in patients with mild renal impairment and doubled in patients with moderate impairment to ESRD (CrCl <50 mL/minute) relative to healthy subjects.

Special Populations: Hepatic Function Impairment

The AUC was increased by ~50% in subjects with moderate hepatic impairment and doubled in subjects with severe hepatic impairment. There was an increase of ~30% in exposure to NAMR in patients with moderate to severe hepatic impairment.

Special Populations: Elderly

The AUC was ~40% to 50% higher and terminal half-life was prolonged by ~30% in elderly patients compared with younger subjects.

Special Populations: Gender

The AUC values were ~20% higher in younger females compared with younger males and ~30% higher in elderly women compared with elderly men. The Cmax values were ~50% higher in younger females compared with younger males and ~100% higher in elderly women compared with elderly men.

Use: Labeled Indications

Partial-onset seizures: As adjunctive treatment for partial-onset seizures in patients ≥18 years 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

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Dosing: Adult

Partial-onset seizures, adjunct: Oral: Initial: 100 mg 3 times daily; may increase at weekly intervals in increments of ≤150 mg per day to a maintenance dose of 200 to 400 mg 3 times daily based on tolerability (maximum: 400 mg 3 times daily [1,200 mg per day]). In clinical trials, no additional benefit and an increase in adverse effects was observed with doses >900 mg per day. Note: If there is no substantial benefit after adequate titration, then discontinue use and consider other treatment options.

Dosing: Geriatric

Partial-onset seizures, adjunct: Oral: Initial: 50 mg 3 times daily; may increase at weekly intervals in increments of ≤150 mg per day to a maximum dose of 250 mg 3 times daily (750 mg per day). Note: If there is no substantial benefit after adequate titration, then discontinue use and consider other treatment options.

Dosing: Renal Impairment

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl <50 mL/minute: Initial: 50 mg 3 times daily; may increase at weekly intervals in increments of ≤150 mg per day to a maximum dose of 200 mg 3 times daily (600 mg per day).

ESRD requiring hemodialysis: Initial: 50 mg 3 times daily; may increase at weekly intervals in increments of ≤150 mg per day to a maximum dose of 200 mg 3 times daily (600 mg per day). Note: Immediately following hemodialysis a single supplemental dose is recommended; if break through seizures occur toward the end of hemodialysis, an additional supplemental dose may be considered at the start of subsequent dialysis sessions.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh 5 to 6): No dosage adjustment necessary.

Moderate impairment (Child-Pugh 7 to 9): Initial: 50 mg 3 times daily; may increase at weekly intervals in increments of ≤150 mg per day to a maximum dose of 250 mg 3 times daily (750 mg per day).

Severe impairment (Child-Pugh >9): Initial: 50 mg 3 times daily; may increase at weekly intervals in increment of ≤150 mg per day to a maximum dose of 200 mg 3 times daily (600 mg per day).

Administration

Administer in 3 equally divided doses daily with or without food. Swallow tablets whole; do not break, crush, dissolve, or chew. If therapy is discontinued, gradually reduce dose over at least 3 weeks unless safety concerns require abrupt withdrawal.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Alcohol (Ethyl): May enhance the adverse/toxic effect of Ezogabine. Alcohol (Ethyl) may increase the serum concentration of Ezogabine. Monitor therapy

Analgesics (Opioid): CNS Depressants may enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Ezogabine. Management: Consider increasing the ezogabine dose when adding carbamazepine. Monitor patients using the combination closely for evidence of adequate ezogabine therapy. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Dimethindene (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fosphenytoin-Phenytoin: May decrease the serum concentration of Ezogabine. Management: Consider increasing the ezogabine dose when adding phenytoin. Patients using this combination should be monitored closely for evidence of adequate ezogabine therapy. Consider therapy modification

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

LamoTRIgine: Ezogabine may decrease the serum concentration of LamoTRIgine. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Consider therapy modification

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Mianserin: May diminish the therapeutic effect of Anticonvulsants. Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Orlistat: May decrease the serum concentration of Anticonvulsants. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Test Interactions

May falsely elevate serum and urine bilirubin assays

Adverse Reactions

>10%:

Central nervous system: Dizziness (dose related; 15% to 32%), drowsiness (dose related; 15% to 27%), fatigue (13% to 16%), confusion (dose related; 4% to 16%), ataxia (dose related; 5% to 12%)

Neuromuscular & skeletal: Tremor (dose related; 10% to 12%)

2% to 10%:

Central nervous system: Vertigo (8% to 9%), memory impairment (dose related; 6% to 9%), dysarthria (2% to 8%), lack of concentration (6% to 7%), aphasia (dose related; 1% to 7%), abnormal gait (dose related; 2% to 6%), disorientation (5%), anxiety (3% to 5%), equilibrium disturbance (dose related; 3% to 5%), paresthesia (3% to 5%), amnesia (3%), dysphasia (1% to 3%), hallucination (≤2%), psychotic symptoms (≤2%)

Dermatologic: Skin discoloration (10%)

Endocrine & metabolic: Weight gain (dose related; 2% to 3%)

Gastrointestinal: Nausea (6% to 9%), constipation (dose related; 4% to 5%), dyspepsia (3%)

Genitourinary: Dysuria (dose related; 1% to 4%), urinary hesitancy (1% to 4%), urine discoloration (dose related; 2% to 3%), urinary retention (≤2%), hematuria (1% to 2%)

Infection: Influenza (4% to 5%)

Neuromuscular & skeletal: Weakness (4% to 6%)

Ophthalmic: Blurred vision (dose related; 4% to 10%), diplopia (6% to 8%)

Frequency not defined:

Cardiovascular: Prolonged Q-T Interval on ECG (mean: 7.7 msec), syncope

Central nervous system: Brain disease, coma, euphoria

Dermatologic: Alopecia, skin rash

Hematologic & oncologic: Leukopenia, neutropenia, thrombocytopenia

Neuromuscular & skeletal: Muscle spasm

Ophthalmic: Nystagmus, retinal pigment changes

Renal: Nephrolithiasis, renal colic

Respiratory: Dyspnea

<2% (Limited to important or life-threatening): Alopecia, hydronephrosis, hyperhidrosis, hypokinesia, increased appetite, increased liver enzymes, maculopathy (acquired vitelliform lesions), peripheral edema, suicidal ideation, suicidal tendencies

ALERT: U.S. Boxed Warning

Retinal abnormalities and potential vision loss:

Ezogabine 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. In addition, macular abnormalities characterized as vitelliform lesions have been observed. These lesions have been identified most consistently with optical coherence tomography imaging.

Some patients with retinal abnormalities have been found to have abnormal visual acuity. It is not possible to determine whether ezogabine caused this decreased visual acuity, because 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 ezogabine. The rate of progression of retinal abnormalities and their reversibility are unknown. Reversibility of retinal pigmentary abnormalities and partial resolution of vitelliform lesions has been reported after discontinuation of ezogabine in some patients.

Only use ezogabine 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 ezogabine.

All patients taking ezogabine should have baseline and periodic (every 6 months) systematic visual monitoring by an ophthalmic professional. Testing should include visual acuity, dilated fundus photography, and optical coherence tomography. Additional testing may include fluorescein angiograms, perimetry, and electroretinograms (ERG).

If retinal pigmentary abnormalities or vision changes are detected, discontinue therapy unless no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss.

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: Dose-related dizziness and somnolence (generally mild-to-moderate) have been reported; effects generally occur during dose titration and appear to diminish with continued use. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Dermatologic effects: Skin discoloration has been reported; typically blue in color (but may also be gray-blue or brown) and is predominantly located on or around the lips, nail beds of the fingers or toes, face and legs; discoloration of the palate, sclera, and conjunctiva may also occur. Skin discoloration developed in ~10% of patients, generally after ≥2 years of treatment and at higher doses (≥900 mg). If detected, consider other treatment options or discontinue use.

• Neuropsychiatric disorders: Dose-related neuropsychiatric disorders, including confusion, psychotic symptoms, and hallucinations, have been reported, generally within the first 8 weeks of treatment; some patients required hospitalization. Symptoms resolved in most patients within 7 days of discontinuation of therapy. The risk appears to be greatest with rapid titration at greater than the recommended doses.

• Ocular complications: [US Boxed Warning]: Retinal abnormalities that may progress to vision loss have been reported and were seen in about one-third of patients after approximately 4 years of treatment. These retinal abnormalities exhibited funduscopic features similar to those of retinal pigment dystrophies. Macular abnormalities characterized as vitelliform lesions have also been observed; these lesions have been identified most consistently with optical coherence tomography imaging. The rate of progression and reversibility of these retinal abnormalities is unknown. Reversibility of retinal pigmentary abnormalities and partial resolution of vitelliform lesions has been reported after discontinuation of ezogabine. Limit use to patients who have responded inadequately to other treatments and in whom the benefits of therapy exceed the risk of vision loss. Visual monitoring (at least visual acuity, dilated fundus photography, and optical coherence tomography) by an ophthalmic professional is recommended at baseline and at 6-month intervals. Other visual tests may include fluorescein angiograms, perimetry, and electroretinograms). Discontinue use if there is no substantial benefit after adequate titration or if retinal pigmentary abnormalities or vision changes are detected. If no other treatment options are available and the benefits of treatment outweigh the potential risk of vision loss, then may cautiously continue treatment with ezogabine.

• QT prolongation: QT prolongation has been observed; monitor ECG in patients with electrolyte abnormalities (eg, hypokalemia, hypomagnesemia), concomitant medications which may augment QT prolongation, or any underlying cardiac abnormality which may also potentiate risk (eg, heart failure, ventricular hypertrophy).

• Suicidal thinking/behavior: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.

• Urinary retention: Urinary retention, including retention requiring catheterization, has been reported, generally within the first 6 months of treatment. All patients should be monitored for urologic symptoms; close monitoring is recommended in patients with other risk factors for urinary retention (eg, benign prostatic hyperplasia), patients unable to communicate clinical symptoms, or patients who use concomitant medications that may affect voiding (eg, anticholinergics).

Disease-related concerns:

• Hepatic impairment: Dosage adjustment recommended in moderate to severe hepatic impairment; ezogabine exposure increases in moderate to severe impairment.

• Renal impairment: Dosage adjustment recommended in patients with CrCl <50 mL/minute renal impairment or patients with end-stage renal disease receiving hemodialysis; ezogabine undergoes significant renal elimination.

Special populations:

• Elderly: Use caution in elderly due to potential for urinary retention, particularly in older men with symptomatic BPH. Systemic exposure is increased in the elderly; dosage adjustment is recommended in patients ≥65 years of age.

Other warnings/precautions:

• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency. Unless safety concerns require a more rapid withdrawal, therapy should be withdrawn gradually over a period of ≥3 weeks to minimize the potential of increased seizure frequency.

Monitoring Parameters

Seizures; electrolytes, bilirubin, QT interval (in patients with risk factors for QT prolongation), renal and hepatic function; urologic symptoms; observe patient for excessive sedation, confusion, psychotic symptoms, and hallucinations; suicidality (eg, suicidal thoughts, depression, behavioral changes); skin discoloration (blue, or gray-blue or brown in color) around the lips, nail beds of fingers or toes, face and legs.

Ophthalmic exams (at least visual acuity testing, dilated fundus photography, and optical coherence tomography) at baseline and 6-month intervals; fluorescein angiograms, optical coherence tomography, perimetry, and electroretinograms may also be considered.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Patients exposed to ezogabine during pregnancy are encouraged to enroll themselves into the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, dizziness, tremors, spinning feeling, anxiety, nausea, or constipation. Have patient report immediately to prescriber skin discoloration, nail discoloration, lip or mouth discoloration, eye discoloration, vision changes, vision loss, seizures, abnormal heartbeat, difficulty speaking, change in balance, difficulty moving, difficulty focusing, memory impairment, confusion, hallucinations, burning or numbness feeling, severe loss of strength and energy, urinary retention, change in amount of urine passed, painful urination, severe dizziness, passing out, agitation, irritability, panic attacks, mood changes, or signs of depression (suicidal ideation, anxiety, emotional instability, or confusion) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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