Eslicarbazepine (Monograph)

Brand name: Aptiom
Drug class: Anticonvulsants, Miscellaneous
- Voltage-gated Sodium Channel Blockers
VA class: CN400
Chemical name: (10S)-10,11-Dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide
Molecular formula: C₁₅H₁₄N₂O₂C₁₇H₁₆N₂O₃
CAS number: 104746-05-5

Introduction

Anticonvulsant; a dibenz[b,f]azepine-5-carboxamide derivative. Eslicarbazepine acetate is a prodrug that is metabolized to eslicarbazepine (S-licarbazepine), the major active metabolite of oxcarbazepine.

Uses for Eslicarbazepine

Seizure Disorders

Management (in combination with other anticonvulsants) of partial-onset seizures in adults.

In longer-term extension studies, reductions in seizure frequency were maintained for at least 1 year.

Controlled comparative trials between eslicarbazepine acetate and oxcarbazepine needed to fully evaluate the relative efficacy and tolerability of these structurally related anticonvulsants (see Actions).

Once-daily dosage regimen may help improve patient compliance.

Eslicarbazepine Dosage and Administration

General

• Avoid abrupt discontinuance; withdraw gradually to minimize potential for increased seizure frequency and status epilepticus. (See Discontinuance of Therapy under Cautions.)

• Closely monitor for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression. (See Suicidality Risk under Cautions.)

Administration

Oral Administration

Administer orally once daily with or without food.

Tablets may be swallowed whole or crushed.

Dosage

Available as eslicarbazepine acetate; dosage expressed in terms of the acetate salt.

Adults

Seizure Disorders

Partial Seizures

Oral

Initially, 400 mg once daily.

Increase to recommended maintenance dosage of 800 mg once daily after 1 week.

May increase to 1.2 g once daily only if patient tolerates 800 mg once daily for at least 1 week. In clinical studies, the 1.2-g daily dosage was associated with increased adverse effects.

In some patients, may initiate therapy with 800 mg once daily if need for additional seizure reduction outweighs risk of increased adverse effects during initiation of therapy.

Concurrent Use of Other Anticonvulsants

Oxcarbazepine: Because eslicarbazepine is the S-enantiomer of the major metabolite of oxcarbazepine, avoid concurrent use.

Carbamazepine: Dosages of eslicarbazepine acetate and/or carbamazepine may require adjustment based on efficacy and tolerability (see Specific Drugs under Interactions).

Other CYP-inducing anticonvulsants (e.g., phenobarbital, phenytoin, primidone): Higher dosages of eslicarbazepine acetate may be necessary (see Specific Drugs under Interactions).

Prescribing Limits

Adults

Seizure Disorders

Partial Seizures

Oral

1.2 g once daily.

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment: No dosage adjustment necessary.

Severe hepatic impairment: Not studied; use not recommended.

Renal Impairment

Mild renal impairment: No dosage adjustment necessary.

Moderate to severe renal impairment (Cl_cr <50 mL/minute): Initially, 200 mg once daily. After 2 weeks, increase dosage to recommended maintenance dosage of 400 mg once daily. Some patients may benefit from the maximum recommended maintenance dosage of 600 mg once daily. (See Renal Impairment under Cautions.)

Geriatric Patients

Routine dosage adjustment based on age not necessary; however, dosage adjustment necessary if Cl_cr <50 mL/minute. (See Geriatric Use under Cautions.)

Gender or Race

Dosage adjustment not required.

Cautions for Eslicarbazepine

Contraindications

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

Warnings/Precautions

Sensitivity Reactions

Serious Dermatologic Reactions

Serious dermatologic reactions, including Stevens-Johnson syndrome (SJS), reported with eslicarbazepine acetate. 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.

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

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

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity

DRESS, also known as multiorgan hypersensitivity, reported; may be fatal or life-threatening. 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.

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

Anaphylactic Reactions and Angioedema

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

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

Other Warnings and Precautions

Suicidality Risk

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%). Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks. Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.

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. Anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality.

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

Hyponatremia

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

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). 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).

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

Neurologic Effects

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. These effects are dose-related and generally occur during dosage titration.

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.

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

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

Discontinuance of Therapy

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

Drug-induced Liver Injury

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.

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

Abnormal Thyroid Function Tests

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

Specific Populations

Pregnancy

Category C.

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

Lactation

Distributed into milk. Discontinue nursing or the drug.

Pediatric Use

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

Geriatric Use

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

Patients ≥60 years of age appear to have a greater risk of adverse neurologic effects. (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. Dosage adjustment is necessary if Cl_cr <50 mL/minute.

Hepatic Impairment

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

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

Renal Impairment

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

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

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

Common Adverse Effects

Dizziness, somnolence, nausea, vomiting, headache, diplopia, fatigue, vertigo, ataxia, blurred vision, tremor.

Drug Interactions

Moderate inhibitor of CYP2C19; may induce CYP3A4.

Does not appear to inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2D6, 2E1, 3A4, nor to induce CYP1A2 or phase II hepatic enzymes involved in glucuronidation or sulfation. Mild activation of UGT1A1-mediated glucuronidation observed in vitro.

Autoinduction of metabolism not observed.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interactions (e.g., decreased eslicarbazepine exposure) with inducers of CYP3A4; higher dosages of eslicarbazepine acetate may be necessary.

Potential pharmacokinetic interactions (e.g., decreased substrate concentrations) with concomitant use of CYP3A4 substrates; higher dosages of the CYP3A4 substrate may be necessary.

Potential pharmacokinetic interactions (e.g., increased substrate concentrations) with concomitant use of CYP2C19 substrates.

Drugs associated with Hyponatremia

Possible increased risk of hyponatremia during concomitant use of other drugs associated with hyponatremia; consider monitoring sodium and chloride concentrations during concurrent therapy.

Specific Drugs

Eslicarbazepine Pharmacokinetics

Absorption

Bioavailability

Following oral administration, eslicarbazepine acetate is rapidly and extensively metabolized by hydrolytic first-pass metabolism to eslicarbazepine; plasma concentrations of the parent drug mostly undetectable.

Food

Food does not affect the pharmacokinetics of eslicarbazepine acetate.

Plasma Concentrations

Peak concentrations of eslicarbazepine occur 1-4 hours following oral administration of eslicarbazepine acetate.

Exhibits linear and dose-proportional pharmacokinetics at recommended dosages.

Steady-state eslicarbazepine concentrations attained 4–5 days after once-daily dosing.

Special Populations

Pharmacokinetics not affected by moderate hepatic impairment (Child-Pugh score 7–9).

Mild renal impairment: Systemic exposure increased by 62%.

Moderate and severe renal impairment: Systemic exposure was 2- and 2.5-fold higher, respectively.

Pharmacokinetic profile similar in geriatric individuals with Cl_cr >60 mL/minute compared with younger healthy adults (18–40 years of age).

Distribution

Extent

Distributes into human milk.

Plasma Protein Binding

<40% (independent of plasma concentration).

Elimination

Metabolism

Rapidly and extensively metabolized to eslicarbazepine via hydrolytic first-pass metabolism.

Eslicarbazepine accounts for 91% of systemic exposure; systemic exposure to minor active metabolites of R-licarbazepine and oxcarbazepine is 5 and 1%, respectively, while the inactive glucuronides of these metabolites account for approximately 3% of systemic exposure.

Elimination Route

Eslicarbazepine and other metabolites primarily eliminated by renal excretion; over 90% of a dose is recovered in urine as unchanged eslicarbazepine (approximately two-thirds) or as glucuronide conjugates (approximately one-third).

Renal clearance of eslicarbazepine is substantially lower than GFR in healthy individuals with normal renal function, suggesting that renal tubular reabsorption occurs.

Half-life

13–20 hours (in patients with epilepsy).

Special Populations

Clearance is reduced in patients with renal impairment and correlates with Cl_cr.

Eslicarbazepine and other metabolites are cleared by repeated hemodialysis in patients with end-stage renal disease.

Pharmacokinetics not substantially affected by gender or race.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

• Exact mechanism of anticonvulsant action not fully elucidated; however, eslicarbazepine acetate, like carbamazepine and oxcarbazepine, is known to reduce excitability of rapidly firing neurons by inhibiting voltage-gated sodium channels.

• Eslicarbazepine binds to voltage-gated sodium channels with a higher affinity for the inactivated state than for the resting state allowing selective inhibition of more rapidly firing neurons.

• Eslicarbazepine is structurally similar to carbamazepine and is the S-enantiomer of racemic licarbazepine, the major metabolite of oxcarbazepine (10-monohydroxy derivative [MHD]).

Advice to Patients

• 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.

• Importance of taking only as prescribed.

• Risk of suicidality (anticonvulsants, including eslicarbazepine acetate, may increase risk of suicidal thoughts or actions in about 1 in 500 people). 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).

• Importance of informing patients and caregivers about the risk of serious, potentially fatal skin reactions. 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.

• Risk of drug reaction with eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity. 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.

• 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. Importance of instructing patients to immediately report such symptoms to their clinician.

• Importance of advising patients that eslicarbazepine acetate can cause hyponatremia, particularly in patients receiving other drugs that can lower serum sodium concentrations. 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).

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

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

• Importance of informing women that eslicarbazepine acetate can substantially decrease the effectiveness of hormonal contraceptives. 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.

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

• 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.

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

Preparations

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.

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