Eslicarbazepine

Usage

Eslicarbazepine is an anticonvulsant medication primarily prescribed for the adjunctive treatment of partial-onset seizures (also known as focal seizures), with or without secondary generalization, in adults, adolescents, and children over 6 years of age. In some cases, it can also be used as monotherapy in adults with newly diagnosed epilepsy. It is also used as adjunctive therapy in patients above 6 years of age, with partial-onset seizures, with or without secondary generalization.

Alternate Names

Eslicarbazepine acetate is the active ingredient. A common brand name is Aptiom®. Zebinix® is a brand name used in some regions.

How It Works

Pharmacodynamics: Eslicarbazepine stabilizes neuronal membranes by modulating voltage-gated sodium channels, inhibiting repetitive neuronal firing. It preferentially targets neurons in a hyperexcitable state. It is the S-enantiomer of the major metabolite of oxcarbazepine.

Pharmacokinetics:

• Absorption: Well-absorbed orally, with peak plasma concentrations reached in 1 to 4 hours. Taking the medication with food does not significantly affect absorption.
• Metabolism: Primarily metabolized in the liver, mainly by CYP3A4, with minor contributions from CYP2C19. It undergoes glucuronidation and is converted to its main metabolite, eslicarbazepine 10,11-diol (also referred to as R-licarbazepine).
• Elimination: Primarily eliminated in the urine (approximately 62%), with a small portion excreted in feces (approximately 20%). The apparent elimination half-life is approximately 10 to 20 hours.

Mode of Action: At a molecular level, eslicarbazepine binds to the alpha subunit of voltage-gated sodium channels in neurons, specifically those in a state of high-frequency firing. It blocks the influx of sodium ions, thus preventing the generation of action potentials and slowing down the propagation of nerve impulses.

Elimination Pathways: Renal excretion and hepatic metabolism are the primary elimination pathways. CYP3A4 and CYP2C19 are the main hepatic enzymes involved.

Dosage

Standard Dosage

Adults:

• Initial: 400 mg orally once daily. Some patients may initiate at 800 mg once daily if the need for seizure control is high.
• Maintenance: 800-1600 mg orally once daily. Titration should occur weekly in increments of 400-600 mg based on clinical response and tolerability. In monotherapy, 1600mg/d is the most common dose, while 1200mg/d is the most common dose for adjunctive therapy.

Children (4-17 years):

Dosage is weight-based and administered once daily.

• 11-21 kg: Initial: 200 mg/day; Maintenance: 400-600 mg/day.
• 22-31 kg: Initial: 300 mg/day; Maintenance: 500-800 mg/day.
• 32-38 kg: Initial: 300 mg/day; Maintenance: 600-900 mg/day.
• >38 kg: Initial: 400 mg/day; Maintenance: 800-1200 mg/day.

Special Cases:

• Elderly Patients: Use with caution, adjusting dose based on renal function and comorbidities. Lower initial and maintenance doses are recommended if creatinine clearance is reduced. The 1600 mg/d dose for monotherapy is not recommended for the elderly.
• Patients with Renal Impairment: Dose adjustment needed.
  • Mild (CrCl >60 ml/min): No adjustment usually needed.
  • Moderate to Severe (CrCl 30-60 ml/min): Initial: 200 mg every other day for 2 weeks; then, 400 mg once daily.
• Patients with Hepatic Dysfunction: No dose adjustment is needed for mild to moderate impairment. Use not recommended in severe hepatic impairment.
• Patients with Comorbid Conditions: Evaluate case by case, considering potential interactions. Caution in those with cardiac conduction abnormalities.

Clinical Use Cases

Eslicarbazepine’s primary indication is for managing partial-onset seizures. Specific dosing in other clinical settings such as intubation, surgery, mechanical ventilation, ICU, or emergencies like status epilepticus or cardiac arrest are not explicitly defined, however, consider co-administration with other AEDs if indicated.

Dosage Adjustments

Dose adjustments may be necessary based on individual patient factors, including renal or hepatic impairment, other medical conditions, concomitant medications, and response to therapy. Therapeutic drug monitoring may be helpful in some situations.

Side Effects

Common Side Effects:

Dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor. These are more common with doses above 800 mg/day.

Rare but Serious Side Effects:

Suicidal ideation, serious skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis), hyponatremia, anaphylaxis, angioedema, severe hepatic dysfunction, blood dyscrasias.

Long-Term Effects:

Chronic complications related to long-term eslicarbazepine use are not well-established but could include cognitive effects and bone health issues.

Adverse Drug Reactions (ADR):

Skin rashes (particularly in patients with HLA-B1502 or HLA-A3101 alleles), drug reaction with eosinophilia and systemic symptoms (DRESS), hyponatremia, and hepatic injury. These can also occur with other AEDs such as carbamazepine and oxcarbazepine.

Contraindications

• Hypersensitivity to eslicarbazepine acetate, oxcarbazepine, or any component of the formulation.
• Second- or third-degree atrioventricular (AV) block.

Drug Interactions

• CYP3A4 Inducers: (e.g., carbamazepine, phenytoin, phenobarbital, rifampin) may decrease eslicarbazepine levels.
• CYP3A4 Inhibitors: (e.g., ketoconazole, itraconazole, erythromycin) may increase eslicarbazepine levels.
• CYP2C19 Inhibitors: (e.g., omeprazole) may increase eslicarbazepine levels.
• Hormonal Contraceptives: Eslicarbazepine can reduce their effectiveness.
• Lamotrigine: Eslicarbazepine may slightly decrease lamotrigine levels.
• Oxcarbazepine: Avoid concomitant use.

Pregnancy and Breastfeeding

• Pregnancy: Limited data are available. Animal studies show developmental toxicity. Use only if the potential benefit outweighs the risk. Consider the North American Antiepileptic Drug (NAAED) Pregnancy Registry.
• Breastfeeding: Eslicarbazepine is present in human milk. Discontinue breastfeeding or consider the risks versus benefits of treatment.

Drug Profile Summary

• Mechanism of Action: Blocks voltage-gated sodium channels, inhibiting neuronal firing.
• Side Effects: Dizziness, somnolence, nausea, headache, diplopia, skin rash, hyponatremia (rare).
• Contraindications: Hypersensitivity, 2nd/3rd-degree AV block.
• Drug Interactions: CYP3A4 inducers/inhibitors, hormonal contraceptives, oxcarbazepine.
• Pregnancy & Breastfeeding: Use with caution, weigh risks and benefits.
• Dosage: Adults: 800-1600 mg/day; Children: weight-based.
• Monitoring Parameters: Sodium levels, liver function tests (periodically).

Popular Combinations

Often combined with other antiepileptic drugs such as lamotrigine, levetiracetam, valproic acid, or lacosamide, depending on seizure type and patient response. The combinations are chosen based on the patient specific factors, including age, comorbidities and individual seizures types.

Precautions

• General Precautions: Monitor sodium levels, liver function, and for signs of hypersensitivity.
• Specific Populations:
  • Pregnant Women: Counsel on risks and benefits.
  • Breastfeeding Mothers: Advise against breastfeeding.
  • Children & Elderly: Weight-based dosing for children, consider age-related changes in the elderly.
• Lifestyle Considerations: May impair driving. Avoid alcohol.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Eslicarbazepine?

A: Adults: 800-1600 mg once daily. Children: weight-based dosing (see above).

Q2: What is the mechanism of action of Eslicarbazepine?

A: It primarily blocks voltage-gated sodium channels, stabilizing neuronal membranes and reducing excitability.

Q3: What are the common side effects of Eslicarbazepine?

A: Dizziness, somnolence, nausea, headache, diplopia.

Q4: What are the serious side effects of Eslicarbazepine?

A: Suicidal ideation, serious skin reactions, hyponatremia, anaphylaxis.

Q5: Can Eslicarbazepine be used during pregnancy?

A: Use with caution if the potential benefit outweighs the risk. Discuss with a specialist.

Q6: Can Eslicarbazepine be used during breastfeeding?

A: It’s generally advised to discontinue breastfeeding or discuss risks versus benefits with a specialist.

Q7: What are the major drug interactions with Eslicarbazepine?

A: CYP3A4 inducers/inhibitors, hormonal contraceptives, oxcarbazepine.

Q8: How should Eslicarbazepine be administered?

A: Orally, once daily, with or without food. Tablets can be swallowed whole or crushed and mixed with a small amount of water or applesauce.

Q9: What should be monitored in patients taking Eslicarbazepine?

A: Sodium levels, liver function tests, and observe for any signs of hypersensitivity reactions like skin rash. Monitor ECG in patients with pre-existing cardiac conduction problems.

Q10: What should patients do if they miss a dose of Eslicarbazepine?

A: Take the missed dose as soon as remembered unless it’s close to the next dose. Do not double the dose.