Eslicarbazepine Acetate

Dosage Forms & Strengths

tablet

• 200mg
• 400mg
• 600mg
• 800mg

Partial-Onset Seizures

Indicated for partial-onset seizures as monotherapy or adjunctive therapy

Initial

• 400 mg PO qDay
• For some patients, treatment may be initiated at 800 mg qDay if the need for additional seizure reduction outweighs an increased risk of adverse reactions during initiation

Titration and maintenance

• Increase dose by weekly increments of 400-600 mg, based on clinical response and tolerability
• Recommended maintenance dose is 800-1600 mg once daily
• Monotherapy: Consider 800 mg/day maintenance dose in patients unable to tolerate 1200 mg/day
• Adjunctive therapy: 1600 mg/day should be considered in patients who did not achieve a satisfactory response with 1200 mg/day

Dosage Modifications

Do not take adjunctively with oxcarbazepine

Coadministration with enzyme-inducing AEDs (eg, carbamazepine, phenytoin, phenobarbital, primidone): May need to increase eslicarbazepine dose

Renal impairment

• Mild (CrCl ≥50 mL/min): No dosage adjustment necessary
• Moderate-to-severe (CrCl <50 mL/min): Reduce the initial, titration, and maintenance doses by 50%; may adjust titration and maintenance doses according to clinical response

Hepatic impairment

• Mild-to-moderate: No dosage adjustment required
• Severe: Not recommended (not studied)

Dosing Considerations

When discontinuing eslicarbazepine acetate, gradually reduce dose and avoid abrupt discontinuation in order to minimize risk of increased seizure frequency and status epilepticus

Dosage Forms & Strengths

tablet

• 200mg
• 400mg
• 600mg
• 800mg

Partial-Onset Seizures

Indicated for partial-onset seizures as monotherapy or adjunctive therapy

<4 years: Safety and efficacy not established

4-17 years

• Recommended initial weight based dosage
  • 11-21 kg: 200 mg PO qDay initially; titration increment not to exceed 200 mg/day
  • 22-38 kg: 300 mg PO qDay; titration increment not to exceed 300 mg/day
  • >38kg: 400 mg PO qDay; titration increment not to exceed 400 mg/day
  • Dosage should be increased based on clinical response and tolerability, no more frequently than once per week
• Maintenance dosage
  • 11-21 kg: Not to exceed 400-600 mg/day
  • 22-31 kg: Not to exceed 500-800 mg/day
  • 32-38 kg: Not to exceed 600-900 mg/day
  • >38kg: Not to exceed 800-1200 mg/day

Dosage Modifications

Do not take adjunctively with oxcarbazepine

Coadministration with enzyme-inducing AEDs (eg, carbamazepine, phenytoin, phenobarbital, primidone): May need to increase eslicarbazepine dose

Renal impairment

• Mild (CrCl ≥50 mL/min): No dosage adjustment necessary
• Moderate-to-severe (CrCl <50 mL/min): Reduce the initial, titration, and maintenance doses by 50%; may adjust titration and maintenance doses according to clinical response

Hepatic impairment

• Mild-to-moderate: No dosage adjustment required
• Severe: Not recommended (not studied)

Dosing Considerations

When discontinuing eslicarbazepine acetate, gradually reduce dose and avoid abrupt discontinuation in order to minimize risk of increased seizure frequency and status epilepticus

Contraindications

• Known hypersensitivity to eslicarbazepine acetate or oxcarbazepine.1 (See Sensitivity Reactions under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Serious dermatologic reactions, including Stevens-Johnson syndrome (SJS), reported with eslicarbazepine acetate.1 Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and SJS, have been reported in patients receiving oxcarbazepine or carbamazepine, which are chemically related to eslicarbazepine acetate.1 13

Monitor patients for dermatologic reactions.1 If a dermatologic reaction occurs, discontinue eslicarbazepine acetate unless reaction is clearly not drug related.1

Do not use in patients who developed a previous dermatologic reaction to either oxcarbazepine or eslicarbazepine acetate.1 (See Contraindications under Cautions.)

DRESS, also known as multiorgan hypersensitivity, reported; may be fatal or life-threatening.1 Clinical presentation is variable but typically presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis sometimes resembling an acute viral infection); eosinophilia is often present.1

Monitor patients for possible hypersensitivity reactions; immediately evaluate patients who develop possible signs and symptoms of DRESS.1 Discontinue drug if another cause cannot be established.1 Do not use eslicarbazepine acetate in patients with a prior DRESS reaction to either oxcarbazepine or eslicarbazepine acetate.1 (See Contraindications under Cautions.)

Rare cases of anaphylaxis and angioedema, which can be fatal, reported.1

Monitor patients for possible hypersensitivity reactions (e.g., breathing difficulties, swelling).1 If such reactions occur, discontinue drug if cannot establish another cause.1 Do not use eslicarbazepine acetate in patients with a prior anaphylactic-type reaction to either oxcarbazepine or eslicarbazepine acetate.1 (See Contraindications under Cautions.)

Other Warnings and Precautions

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).1 10 11 12 Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.1 10 11 Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1 10

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.1 10 11 12 Anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality.1 10

Balance risk of suicidality with risk of untreated illness.1 10 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.1 12 If suicidal thoughts or behavior emerges during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.1 12 (See Advice to Patients.)

Clinically important hyponatremia (serum sodium concentrations <125 mEq/L) reported.1 2 Hyponatremia is dose related and generally develops during the first 8 weeks of therapy, possibly as early as after 3 days.1 Serious, life-threatening complications, which necessitated hospitalization and drug discontinuance, occurred in some patients.1 Concurrent hypochloremia also was present.1

Consider monitoring serum sodium and chloride concentrations during maintenance therapy, particularly in patients concurrently receiving other drugs known to decrease serum sodium concentrations (e.g., carbamazepine, desmopressin, diuretics).1 25 Measure sodium and chloride concentrations in patients who develop symptoms of hyponatremia (e.g., nausea, vomiting, malaise, headache, lethargy, confusion, irritability, muscle weakness or spasms, obtundation, increase in seizure frequency or severity).1

If hyponatremia occurs, dosage reduction or drug discontinuance may be necessary.1

Adverse neurologic effects may occur; dizziness, disturbances in gait or coordination (e.g., ataxia, vertigo, balance disorder, nystagmus, abnormal coordination), somnolence and fatigue, cognitive dysfunction (e.g., memory impairment, disturbance in attention, amnesia, confusional state, aphasia, speech disorder, slowness of thought, disorientation, psychomotor retardation), and visual changes (e.g., diplopia, blurred vision, visual impairment) reported.1 These effects are dose-related and generally occur during dosage titration.1

Risk of some adverse neurologic effects (e.g., dizziness, disturbances in gait or coordination, visual changes) appears to be greater in patients ≥60 years of age.1

Dizziness and diplopia occur more frequently during concurrent use of carbamazepine; dosage adjustment of eslicarbazepine acetate and/or carbamazepine may be necessary.1 (See Specific Drugs under Interactions.)

Caution patients about possible neurologic effects during therapy.1 (See Advice to Patients.)

Abrupt withdrawal of anticonvulsants may result in increased seizure frequency and status epilepticus in patients with seizure disorders.1 Withdraw eslicarbazepine acetate gradually.1

Adverse hepatic effects, ranging from mild to moderate transaminase elevations (>3 times the ULN) to rare cases with concomitant elevations of total bilirubin (>2 times the ULN) reported.1

Manufacturer recommends baseline liver function tests.1 Discontinue eslicarbazepine acetate in patients with jaundice or other evidence of substantial liver injury (i.e., laboratory evidence).1

Dose-dependent decreases in serum thyroid hormone concentrations (free and total triiodothyronine [T3] and thyroxine [T4]) observed.1 These changes were not associated with other abnormal thyroid function test results suggesting hypothyroidism.1 Clinical evaluation of abnormal thyroid test results is recommended.1

Specific Populations

Category C.1

North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 (for patients and caregivers); NAAED registry information also available on the website .1

Distributed into milk.1 Discontinue nursing or the drug.1

Safety and efficacy not established in patients <18 years of age; not FDA-labeled for use in pediatric patients.1 23 However, pharmacokinetics, efficacy, and tolerability have been studied in a limited number of pediatric patients 2–17 years of age with partial-onset seizures.22 23

Insufficient experience in patients ≥65 years of age to establish efficacy in this population.1

Patients ≥60 years of age appear to have a greater risk of adverse neurologic effects.1 (See Neurologic Effects under Cautions.)

Although pharmacokinetics do not appear to be affected by age independently (see Absorption: Special Populations, under Pharmacokinetics), consider greater frequency of renal impairment and concomitant medical conditions and medications when selecting dosage in geriatric patients.1 Dosage adjustment is necessary if Clcr <50 mL/minute.1

Pharmacokinetics not affected by moderate hepatic impairment; dosage adjustment not necessary in patients with mild or moderate hepatic impairment.1

Not studied in patients with severe hepatic impairment; use not recommended.1

Eslicarbazepine and other metabolites are primarily eliminated by renal excretion.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Dosage adjustment not necessary in patients with mild renal impairment.1 However, dosage adjustment is recommended in patients with moderate or severe renal impairment (Clcr <50 mL/minute).1 (See Renal Impairment under Dosage and Administration.)

Repeated hemodialysis removes eslicarbazepine and other metabolites from systemic circulation in patients with end-stage renal disease.1

Common Adverse Effects

Dizziness,1 2 3 4 somnolence,1 2 3 4 nausea,1 2 3 4 vomiting,1 2 3 4 headache,1 2 3 4 diplopia,1 2 3 4 fatigue,1 3 vertigo,1 2 4 ataxia,1 blurred vision,1 3 tremor.1

Storage

Oral

20–25°C (may be exposed to 15–30°C).1

• Importance of providing patient with a copy of manufacturer's patient information (medication guide) when therapy is initiated and each time the drug is dispensed.1

• Importance of taking only as prescribed.1

• Risk of suicidality (anticonvulsants, including eslicarbazepine acetate, may increase risk of suicidal thoughts or actions in about 1 in 500 people).1 10 12 Importance of patients, family members, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).1 10

• Importance of informing patients and caregivers about the risk of serious, potentially fatal skin reactions.1 Importance of informing patients about the signs and symptoms that may signal a serious skin reaction and instructing patients to immediately consult with their clinician if a skin reaction occurs during treatment.1

• Risk of drug reaction with eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity.1 Importance of advising patients that a fever associated with signs of other organ system involvement (e.g., rash, lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their clinician immediately.1

• Importance of advising patients of life-threatening symptoms suggesting anaphylaxis or angioedema (e.g., swelling of the face, eyes, tongue; difficulty swallowing or breathing) that may occur.1 Importance of instructing patients to immediately report such symptoms to their clinician.1

• Importance of advising patients that eslicarbazepine acetate can cause hyponatremia, particularly in patients receiving other drugs that can lower serum sodium concentrations.1 Patients should be advised to promptly contact their clinician if they develop any symptoms of hyponatremia (e.g., nausea, tiredness, lack of energy, irritability, confusion, muscle weakness or spasms, increase in seizure frequency or severity).1

• Importance of advising patients of risk of adverse neurologic effects such as dizziness, gait disturbance, somnolence, fatigue, cognitive dysfunction, and visual disturbances.1 These effects are more likely to occur during the dosage titration phase (compared with the maintenance phase).1 Importance of advising patients not to drive, operate machinery, or engage in other hazardous activities until the effects of drug therapy are known.1

• Importance of advising patients not to discontinue eslicarbazepine acetate therapy without consulting with their clinician.1 The drug should be gradually withdrawn to minimize the risk of increased seizure frequency and status epilepticus.1

• Importance of informing women that eslicarbazepine acetate can substantially decrease the effectiveness of hormonal contraceptives.1 8 Women of childbearing potential should be advised to use additional or alternative nonhormonal forms of contraception during therapy and for at least one menstrual cycle after discontinuance or until otherwise instructed by their clinician.1 8

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of clinicians informing women about the existence of and encouraging enrollment in the pregnancy registry (see Pregnancy under Cautions).1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., kidney or liver disease) or history of suicidality, depression, or mood disorder.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.