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:

  • In individuals older than or equal to 18 years old who have responded poorly to a number of different treatments and for whom the advantages outweigh the risk of retinal abnormalities and potential reduction in visual acuity. As an adjuvant treatment for partial-onset seizures.

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: The first dose is 100 mg three times per day; the dose may be increased at weekly intervals in increments of greater than or equal to 150 mg per day to a maintenance dose of 200 to 400 mg three times per day, depending on the patient's tolerance.
  The maximum dose is 1,200 mg per day, or 400 mg three times a day.
  In clinical trials, doses greater than 900 mg per day did not produce any additional benefits and actually increased the negative effects.

Note:

• Even if there is no significant improvement after sufficient titration, we can stop using it and look into alternative treatments.

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 change is required.

• CrCl <50 mL/minute:

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

• ESRD requiring hemodialysis:

  • Initial: 50 mg 3 times a day;
  • May be increased to a maximum dose of 200 mg three times per day at weekly intervals in increments of less than or equal to 150 mg per 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 change in dose is necessary.

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

  • Initial dose: 50 mg three times daily; may be increased at weekly intervals in increments of no more than 150 mg daily and no more than 250 mg three times daily (750 mg per day).

• Severe impairment (Child-Pugh >9):

  • Initial dose: 50 mg three times daily; may be increased at weekly intervals in increments of no more than 150 mg daily, up to a maximum dose of 200 mg three times daily (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 complaints of dose-related drowsiness and lightheadedness (generally mild to moderate).
  • These side effects typically appear during dose adjustment and appear to diminish over time.

• 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.
  • 10% of patients may have skin discoloration. This frequently occurs at larger doses (>=900mg) or after more than two years of medication.
  • If you suspect that the patient is suffering from a condition, consider other options or stop using it.

• Neuropsychiatric disorders

  • In the first eight weeks of therapy, cases of dose-related neuropsychiatric problems such disorientation, psychotic symptoms, and hallucinations have been documented. Some patients required admission.
  • 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.
  • Similar funduscopic characteristics to those found in retinal pigment dystrophies were present in these retinal abnormalities.
  • 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.
  • The use of this medicine should be restricted to patients who have not responded to prior treatments or in whom the potential benefits outweigh the risks of visual loss.
  • An ophthalmic professional should perform visual monitoring at baseline and every 6 months.
  • Fluorescein angiograms and perimetry are other options for visual testing.
  • Discontinue use if appropriate titration shows no discernible effect, or if anomalies in eyesight or retinal pigmentation are discovered.
  • You may proceed cautiously with ezogabine if there are no better options and the potential dangers of visual loss exceed the advantages.

• Extension of QT

  • QT prolongation has already been documented.
  • In patients with electrolyte abnormalities (such as hypokalemia or hypermagnesemia), concurrent medications that could lengthen QT intervals, or any other cardiac abnormality that could potentially raise risk, keep an eye on their ECGs (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.
  • Any signs of urology should be properly watched in patients.
  • Patients who have other risk factors, such as benign prostatic hyperplasia, patients who are unable to convey their symptoms, or patients who take anticholinergic medications should pay particular attention to this.

• Hepatic impairment

  • Dosage modification is necessary for moderate to severe hepatic impairment. In cases of severe impairment, ezogabine exposure is increased.

• Renal impairment

  • Patients receiving hemodialysis for end-stage renal disease and those with renal impairment defined as CrCl 50mL/min should alter their dosage. Ezogabine is significantly eliminated via the kidneys.

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
• Look for symptoms of severe sedation, disorientation, and psychosis in the patient.
  suicidality (eg suicidal thoughts and depression, behavioural changes) (eg suicidal thoughts and depression, behaviour changes)
• Around the lips and toes, there is skin discoloration (blue, gray-blue, or brown).
• At baseline and every six months, ophthalmic exams, including at least visual acuity, dilated fundus photography, and optical coherence tomography, can be done.
• It may also be feasible to perform fluorescein angiograms, optical coherence tomography, perimetry, and electroretinograms.

How to administer Retigabine (Ezogabine)?

• Each day, with or without food, take 3 equally sized doses of the tablet.
• 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 voltage-gated potassium channel KCNQ (Kv7.2-7.5).
• This strengthens the M-current while stabilising the open configuration.
• As a result, epileptiform activity is repressed and neuronal excitability is regulated.
• 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.