Retigabine (Ezogabine) is an anticonvulsant and modulates potassium channels. It is used as an adjunctive treatment in adults with partial-onset seizures.

Retigabine (Ezogabine) Uses:

• Partial-onset seizures:

  • As adjunctive treatment for partial-onset seizures in patients greater or equal to the age of 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.

Retigabine (Ezogabine) Dose in Adults

Note: More than 1 year in the US, Potiga has been discontinued.

Retigabine (Ezogabine) Dose in the Partial-onset seizures as an adjunctive treatment:

• Oral: Initial: 100 mg thrice a day;
• may increase at weekly intervals in increments of greater or equal to 150 mg per day to a maintenance dose of 200 to 400 mg thrice a day depending on the tolerability.
• The maximum dose is 400 mg 3 times in a day or 1,200 mg per day.
• In clinical trials, no additional benefit and an increase in adverse effects were observed with doses greater than 900 mg every day.

Note:

• We can discontinue use and consider other treatment options even if there is no substantial benefit after adequate titration.

Use in Children:

Not indicated.

Retigabine (Ezogabine) Pregnancy Risk Factor C

• Patients who have been exposed to ezogabine in pregnancy should call 1-888-233-2334. Additional information can be found at aedpregnancyregistry.org.
• Animal reproduction studies have shown that adverse events can be observed.

Use of ezogabine during lactation

• It is unknown if ezogabine can be found in breast milk.
• Manufacturer recommends that a decision is made about whether to continue nursing or discontinue the drug.
• This consideration should be taken in light of the possibility of serious adverse reactions in the infant's nursing baby.

Retigabine (Ezogabine) Dose in Kidney Disease:

• CrCl ≥50 mL/minute:

  • No dosage adjustment is necessary.

• CrCl <50 mL/minute:

  • Initial: 50 mg 3 thrice in a day;
  • may increase at weekly intervals in increments of less than or equal to 150 mg per day to a maximum dose of 200 mg thrice in a day(600 mg per day).

• ESRD requiring hemodialysis:

  • Initial: 50 mg 3 times a day;
  • may increase at weekly intervals in increments of less than or equal to 150 mg per day to a maximum dose of 200 mg 3 thrice a day(600 mg per day).

Note:

• Immediately following hemodialysis a single supplemental dose is recommended; if breakthrough seizures occur toward the end of hemodialysis, an additional supplemental dose may be considered at the start of subsequent dialysis sessions.

Retigabine (Ezogabine) Dose in Liver Disease:

• Mild impairment (Child-Pugh 5 to 6):

  • No dosage adjustment required.

• Moderate impairment (Child-Pugh 7 to 9):

  • Initial: 50 mg thrice in a day; may increase at weekly intervals in increments of less than or equal to 150 mg per day to a maximum dose of 250 mg 3 times in a day (750 mg per day).

• Severe impairment (Child-Pugh >9):

  • Initial: 50 mg 3 times in a day; may increase at weekly intervals in an increment of less than or equal to 150 mg per day to a maximum dose of 200 mg 3 times in a day (600 mg per day).

Common Side Effects of Retigabine (Ezogabine):

• Central Nervous System:

  • Fatigue
  • Confusion
  • Ataxia
  • Dizziness
  • Drowsiness

• Neuromuscular & Skeletal:

  • Tremor

Less Common Side Effects Of Retigabine (Ezogabine):

• Central Nervous System:

  • Abnormal Gait
  • Disorientation
  • Anxiety
  • Equilibrium Disturbance
  • Paresthesia
  • Amnesia
  • Dysphasia
  • Hallucination
  • Psychotic Symptoms
  • Vertigo
  • Memory Impairment
  • Dysarthria
  • Lack Of Concentration
  • Aphasia

• Dermatologic:

  • Skin Discoloration

• Endocrine & Metabolic:

  • Weight Gain

• Gastrointestinal:

  • Nausea
  • Constipation
  • Dyspepsia

• Genitourinary:

  • Dysuria
  • Urinary Hesitancy
  • Urine Discoloration
  • Urinary Retention
  • Hematuria

• Infection:

  • Influenza

• Neuromuscular & Skeletal:

  • Weakness

• Ophthalmic:

  • Blurred Vision
  • Diplopia

Rare Side effects of Retigabine (Ezogabine):

• 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

Contraindications to Retigabine (Ezogabine):

• The manufacturer's labeling does not list any contraindications.

Warnings and precautions

• CNS effects

  • It is important to warn patients about tasks that require mental alertness, such as driving or operating machinery.
  • There have been reports of dose-related somnolence and dizziness (generally mild to moderate).
  • These effects usually occur during dose adjustment and seem to decrease with continued use.

• Dermatologic effects

  • There have been reports of skin discoloration. It is usually blue, but may also appear gray-blue or be brown.
  • This occurs mainly around the nails, lips, fingers, toes, feet, and face.
  • It is possible to develop discoloration of the palate, skin, and conjunctiva.
  • The skin can become discolored in 10% of patients. This is usually after >=2 year of treatment or at higher doses (>=900mg).
  • If you suspect that the patient is suffering from a condition, consider other options or stop using it.

• Neuropsychiatric disorders

  • Dose-related neuropsychiatric disorders such as confusion, psychotic symptoms and hallucinations have been reported in the first eight weeks of treatment. Some patients had to be admitted.
  • Rapid titration at higher than recommended doses appears to increase the risk.
  • Most patients experienced relief within seven days after discontinuing therapy.

• Ocular complications: [US-Boxed Warning]

  • After approximately four years of treatment, about one-third (or less) of patients have experienced retinal abnormalities that could lead to vision loss.
  • These retinal anomalies displayed funduscopic features that were similar to those seen in retinal pigment dystrophies.
  • Also, vitelliform lesions are a type of macular abnormality that has been seen. These lesions were most easily identified using optical coherence imaging.
  • It is not known how these retinal abnormalities will progress or if they can be reversed.
  • After discontinuation of ezogabine, it has been reported that there was a partial resolution of vitelliform lesion and reversibility of retinal pigmentary abnormalities.
  • Patients who have not responded to other treatments or in whom the potential benefits outweigh the risks of vision loss should be restricted from using this medication.
  • An ophthalmic professional should perform visual monitoring at baseline and every 6 months.
  • Fluorescein angiograms and perimetry are other options for visual testing.
  • If there is no significant benefit after adequate titration, or if vision abnormalities or retinal pigmentary abnormalities are found, discontinue use.
  • If there are no other options and the potential risks of vision loss outweigh the benefits, you may continue with ezogabine cautiously.

• Extension of QT

  • QT prolongation has already been documented.
  • Monitor ECG in patients with electrolyte anomalies (eg. hypokalemia, hypermagnesemia), concomitant medication which may increase QT prolongation or any other cardiac abnormality that may also potentially potentiate risk (eg heart failure, ventricular hypertrophy).

• Suicidal thoughts and behaviors:

  • A pooled analysis of antiepileptic trials (regardless the indication) revealed an increase in suicidal thoughts/behavior.
  • The incidence rate was 0.43% for patients treated, compared to 0.2% for patients who received placebo.
  • Suicidal tendencies can be detected as soon as therapy begins. This is true even if the therapy is ongoing for a week.
  • For any changes in behavior that could indicate depression or suicidal thoughts, monitor all patients.
  • If symptoms develop, immediately alert your healthcare provider.

• Urinary retention

  • Reports of urinary retention have been common, usually within the first six months of treatment. This includes retention that requires catheterization.
  • Patients should be closely monitored for any urologic symptoms.
  • This is especially important for patients with other risk factors such as benign prostatic hyperplasia, patients who are unable to communicate their symptoms or those taking anticholinergics.

• Hepatic impairment

  • Moderate to severe hepatic impairment requires dosage adjustment. Ezogabine exposure is increased in severe impairment.

• Renal impairment

  • Patients with CrCl 50mL/minute renal impairment and patients receiving hemodialysis for end-stage renal disease should adjust their dosage. Ezogabine is subject to significant renal elimination.

Ezogabine (retigabine): Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Seizures
• Electrolytes
• Bilirubin
• QT interval in patients at risk for QT prolongation
• Renal and hepatic function
• Urologic symptoms
• Examine the patient for signs of excessive sedation, confusion and psychotic symptoms.
• suicidality (eg suicidal thoughts and depression, behavior changes)
• Skin discoloration (blue, gray-blue, brown) around the lips and toes.
• Ophthalmic exams at least visual acuity, dilated funds photography and optical coherencetomography may be performed at baseline and six-month intervals.
• Fluorescein angiograms and optical coherencetomography, perimetry and electroretinograms might also be possible.

How to administer Retigabine (Ezogabine)?

• Take 3 equal doses of the tablet daily, with or without food. Take the tablets whole.
• Do not crush, break, dissolve, chew, or smash them.
• Reduce the dosage gradually over a minimum of 3 weeks, unless you have safety concerns or need to stop abruptly.

Mechanism of action of Retigabine (Ezogabine):

• Ezogabine binds to the KCNQ (Kv7.2-7.5) voltage-gated potassium channel channels.
• This stabilizes the open formation and enhances the M-current.
• This results in neuronal excitability being controlled and epileptiform activities being suppressed.
• Ezogabine can also be used to enhance GABA-mediated currents, which may have therapeutic effects.

Absorption:

• Rapid

Protein binding:

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

Metabolism:

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

Bioavailability: Oral:

• About 60%

Half-life elimination:

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

Time to peak plasma:

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

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)

International Brand Names of Retigabine (Ezogabine):

• Potiga
• Trobalt

Retigabine (Ezogabine) Brand Names in Pakistan:

No Brands Available in Pakistan.