Ezogabine

Ezogabine is an anti-epileptic drug, also called an anticonvulsant.

Ezogabine is used to treat partial-onset seizures in adults.

Ezogabine may also be used for purposes not listed in this medication guide.

Ezogabine can cause abnormal changes in your retina (the membrane layer inside your eye that helps produce vision). These changes may cause vision changes that could be permanent.

Your vision will need to be checked before you start taking ezogabine, and every 6 months while you are taking it.

Call your doctor at once if you have any changes in your vision.

You should not use ezogabine if you are allergic to it.

To make sure ezogabine is safe for you, tell your doctor if you have:

• kidney disease;
• liver disease;
• an enlarged prostate or urination problems;
• heart disease or a heart rhythm disorder;
• a history of depression, mental illness, or suicidal thoughts or actions;
• a personal or family history of Long QT syndrome; or
• an electrolyte imbalance (such as low levels of potassium or magnesium in your blood).

Long-term use of ezogabine has caused a blue-colored appearance of the skin or eyes in some people. This effect was seen mainly in the lips, face, legs, fingernails, and toenails. You should have your eyes checked before you start taking ezogabine.

Ezogabine may be habit forming. Never share ezogabine with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it.

FDA pregnancy category C. It is not known whether ezogabine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of ezogabine on the baby.

It is not known whether ezogabine passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using ezogabine.

Do not give this medication to anyone under 18 years old without medical advice.

This medication may cause blurred vision and may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly.

Drinking alcohol can increase certain side effects of ezogabine.

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with ezogabine, especially:

• carbamazepine;
• digoxin; or
• phenytoin.

This list is not complete. Other drugs may interact with ezogabine, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

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.

Tell your healthcare provider if you are breastfeeding or plan to breastfeed. It is not known if ezogabine passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take ezogabine. You and your healthcare provider should decide if you will take ezogabine or breastfeed. You should not do both.

Store this medication at room temperature at 59°F to 86°F (15°C to 30°C).

Keep ezogabine and all medicines out of the reach of children.

This medication is a controlled substance (CV) because it can be abused or lead to drug dependence. Keep your ezogabine in a safe place to protect it from theft. Never give your medication to anyone else because it may harm them. Selling or giving away this medicine is against the law.

Usual Adult Dose for Seizures:

-Initial dose: 100 mg orally 3 times a day for 1 week.
-Titration: Gradual dosage increase of no more than 50 mg orally 3 times a day, at weekly intervals.
-Maintenance dose: 200 mg to 400 mg orally 3 times a day, based on individual patient response and tolerability.
-Maximum dose: 400 mg orally 3 times a day.

Comments:
-If this drug is discontinued, the dosage should be gradually reduced over a period of at least 3 weeks, unless safety concerns require abrupt withdrawal.

Use: Adjunctive treatment of partial-onset seizures in patients aged 18 years and older 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.

Usual Geriatric Dose for Seizures:

Patients aged 65 years and older:
-Initial dose: 50 mg orally 3 times a day for 1 week.
-Titration: Gradual dosage increase of no more than 50 mg orally 3 times a day, at weekly intervals.
-Maximum dose: 250 mg orally 3 times a day.

Comments:
-If this drug is discontinued, the dosage should be gradually reduced over a period of at least 3 weeks, unless safety concerns require abrupt withdrawal.

Use: Adjunctive treatment of partial-onset seizures in patients aged 18 years and older 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.

Neither ezogabine nor its active N-acetyl metabolite (NAMR) is metabolized by CYP enzymes in vitro.1

Does not appear to inhibit CYP1A2, 2A6, 2B6 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5.1 Ezogabine and its NAMR metabolite do not induce CYP1A2 and 3A4/5.1

Neither a substrate nor inhibitor of P-glycoprotein (P-gp); however, NAMR metabolite inhibits P-gp.1

Not an inhibitor of organic cation transporter (OCT) 2 or organic anion transporter (OAT) 1, but weak inhibitor of OAT 3.1

Metabolized by uridine diphosphate-glucuronosyltransferase (UGT) 1A4 and, to a lesser extent, by UGT1A1, 1A3, and 1A9.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP isoenzymes: Pharmacokinetic interactions unlikely.1

Drugs metabolized by major CYP isoenzymes: Pharmacokinetic interactions unlikely.1

Drugs Affected by the P-glycoprotein Transport System

P-gp substrates: Potential pharmacokinetic interaction (increased concentrations of substrate drug).1

Drugs Affecting Uridine Diphosphate-glucuronosyltransferase

UGT inducers: Potential pharmacokinetic interaction (decreased ezogabine concentrations).1

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT-interval prolongation).1 Monitor QT interval.1 (See Prolongation of QT Interval under Cautions.)

Protein-bound Drugs

Clinically important pharmacokinetic interactions unlikely.1

Specific Drugs and Laboratory Tests

Absorption

Bioavailability

Rapidly absorbed following oral administration; peak plasma concentrations generally achieved within 0.5–2 hours.1 3 4 7 16 23 25 26 29 Exhibits dose-proportional, linear pharmacokinetics with no expected accumulation with repeated administration.1 23

Absolute bioavailability of oral ezogabine is approximately 60%.1

Food

Administration with a high-fat meal increased peak plasma concentrations by approximately 38% and delayed time to peak concentrations by 0.75 hour, but did not affect extent of absorption.1 3 4 6 7

Special Populations

Systemic exposure is increased by approximately 50% in individuals with moderate (Child-Pugh score 7–9) hepatic impairment and by approximately 100% in those with severe (Child-Pugh score >9) hepatic impairment.1 20 Systemic exposure not affected by mild (Child-Pugh score 5–6) hepatic impairment.1

Systemic exposure is increased by approximately 30% in individuals with mild renal impairment (Clcr 50–80 mL/minute) and by approximately 100% in those with moderate to severe renal impairment (Clcr <50 mL/minute).1 20

Distribution

Extent

Appears to be well distributed.1

Not known whether distributed into human milk; ezogabine and/or its metabolites distribute into milk in rats.1

Plasma Protein Binding

Ezogabine: Approximately 80%.1 7 16

Active NAMR metabolite: Approximately 45%.1

Elimination

Metabolism

Extensively metabolized in the liver via glucuronidation and acetylation; does not appear to undergo oxidative metabolism via CYP isoenzymes.1 6 7 16 21 22 28

Metabolized to inactive N-glucuronide conjugates by UGT1A1, 1A3, 1A4, and 1A9.1 21 28 Also converted to an N-acetyl (NAMR) metabolite, which is pharmacologically active but to a lesser extent than the parent drug.1 16 21

Elimination Route

Approximately 85% of an orally administered dose is recovered in urine as unchanged drug and metabolites, and 14% in feces mainly as metabolites.1 7 16 26

Half-life

Approximately 7–11 hours for both ezogabine and its NAMR metabolite.1 26

Special Populations

Clearance was reduced and elimination half-life prolonged (by about 30%) in healthy geriatric individuals compared with healthy younger adults.1 26 32 Such decreased clearance may be due, at least in part, to an age-related decline in renal function.6 20 26

Hemodialysis reduces plasma concentrations of ezogabine and its NAMR metabolite by approximately 50%.32

Ezogabine is used together with other medicines to control partial seizures (convulsions) in the treatment of epilepsy.

Ezogabine belongs to a class of medicines called anticonvulsants. It acts in the brain to prevent seizures. However, ezogabine cannot cure epilepsy and will only work to control seizures as long as you continue to take it.

ezogabine is available only with your doctor's prescription.

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it.

Check with your doctor right away if blurred vision or vision changes occur with ezogabine. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

ezogabine may cause problems with urination. Call you doctor right away if you have trouble emptying your bladder or pain while urinating.

Using ezogabine for a long time may cause your skin, nails, lips, mouth, or eyes to have a blue or brown color. Tell your doctor right away if you notice any color changes with ezogabine.

Ezogabine may cause some people to be agitated, irritable, or display other abnormal behaviors, such as feeling sad or hopeless, getting upset easily, or feeling nervous, restless, or hostile. It may also cause some people to have suicidal thoughts and tendencies or to become more depressed. If you notice any of these adverse effects, tell your doctor right away.

Ezogabine may cause some people to become dizzy, drowsy, or have blurred vision or double vision. Make sure you know how you react to ezogabine before you drive, use machines, or do anything else that could be dangerous if you are not alert or not able to see well. If these reactions are especially bothersome, check with your doctor.

Contact your doctor right away if you have symptoms of heart rhythm problems such as feeling dizzy, feeling faint, or having a fast, pounding, or uneven heartbeat. Make sure your doctor knows if you or anyone in your family has ever had a heart rhythm problem such as QT prolongation.

Do not suddenly stop taking ezogabine without checking first with your doctor. If you have been instructed to stop taking ezogabine, ask your doctor how to slowly decrease the dose. This will decrease your chance of having more seizures.

ezogabine may be habit-forming. If you feel that the medicine is not working as well, do not use more than your prescribed dose. Call your doctor for instructions.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

• If you have an allergy to ezogabine or any other part of ezogabine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are breast-feeding or plan to breast-feed.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take ezogabine. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine affects you.
• Follow laws about driving with a seizure problem.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take ezogabine.
• Talk with your doctor before you drink alcohol or use other drugs and natural products that slow your actions.
• This medicine can cause a change in color of your skin, nails, lips, roof of your mouth, and parts of the eye. The changes in color may be blue, grey-blue, or brown. Most of the time, this has happened after at least 2 years of using this medicine but it may happen before then. It is not known if the change in color will go away after stopping ezogabine. Talk with your doctor if this happens.
• If you are 65 or older, use this medicine with care. You could have more side effects.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using ezogabine while you are pregnant.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time ezogabine is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take ezogabine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to ezogabine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

• Anticonvulsant, Neuronal Potassium Channel Opener

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

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.

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.

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.

Applies to ezogabine: oral tablet

Ocular

Very common (10% or more): Retinal pigmentary abnormalities (up to 30%)
Common (1% to 10%): Diplopia, blurred vision
Frequency not reported: Decreased visual acuity, nystagmus
Postmarketing reports: Acquired vitelliform lesions[Ref]

Dermatologic

Very common (10% or more): Discoloration of the skin, palate, scleral, nail, conjunctiva, lip, and/or mucous membrane (up to 40%)
Uncommon (0.1% to 1%): Hyperhidrosis, skin rash
Frequency not reported: Alopecia[Ref]

Psychiatric

Common (1% to 10%): Confusional state, psychotic disorders, hallucinations, anxiety, disorientation
Frequency not reported: Euphoric mood[Ref]

Nervous system

Very common (10% or more): Dizziness (up to 23%), somnolence (up to 22%)
Common (1% to 10%): Memory impairment, tremor, vertigo, abnormal coordination, disturbance in attention, gait disturbance, aphasia, dysarthria, balance disorder, paresthesia, amnesia, myoclonus
Frequency not reported: Syncope, coma, encephalopathy[Ref]

Genitourinary

Common (1% to 10%): Urinary retention, urinary hesitation, dysuria, hematuria, chromaturia[Ref]

Gastrointestinal

Common (1% to 10%): Nausea, constipation, dyspepsia, dry mouth
Uncommon (0.1% to 1%): Dysphasia[Ref]

Hematologic

Frequency not reported: Leukopenia, neutropenia, thrombocytopenia[Ref]

Hepatic

Common (1% to 10%): Increased liver enzymes (less than 2%)
Frequency not reported: Nephrolithiasis[Ref]

Immunologic

Common (1% to 10%): Influenza[Ref]

Metabolic

Common (1% to 10%): Increased weight, increased appetite[Ref]

Musculoskeletal

Uncommon (0.1% to 1%): Hypokinesia
Frequency not reported: Muscle spasms[Ref]

Other

Very common (10% or more): Fatigue (up to 15%)
Common (1% to 10%): Asthenia, malaise, peripheral edema[Ref]

Renal

Uncommon (0.1% to 1%): Nephrolithiasis
Frequency not reported: Renal colic[Ref]

Respiratory

Frequency not reported: Dyspnea[Ref]

Some side effects of ezogabine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Administration Advice:
-Take this drug with or without food.
-Swallow tablets whole; do not chew, crush, or divide drug tablets.

General:
-Clinical trials showed limited evidence of additional improvement in seizure reduction but an increase in adverse events and discontinuations with dosage of 1,200 mg per day compared with 900 mg per day.
-Unless no other suitable treatment options are available and the benefits outweigh the potential risk of vision loss, treatment should be discontinued in patients who fail to show substantial clinical benefit after adequate titration or if retinal pigmentary abnormalities or vision changes are detected.
-Patients who cannot be monitored should usually not be treated with this drug.

Monitoring:
-Cardiovascular: QT interval
-Dermatologic: Skin discoloration
-Genitourinary: Urologic symptoms
-Nervous System: Dizziness and somnolence
-Ocular: Visual function testing (baseline and every 6 months)
-Psychiatric: Confusional state, psychotic symptoms, hallucinations, depression, suicidal thoughts/behaviors, unusual changes in mood/behavior

Patient Advice:
-This drug may cause dizziness, drowsiness, and vision problems; avoid driving and other activities such as operating machinery until you know how this drug affects you.