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Eslicarbazepine (Monograph)

Brand name: Aptiom
Drug class: Ion Channel Inhibition Agents
- Voltage-gated Sodium Channel Blockers

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

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

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 (Clcr <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 Clcr <50 mL/minute. (See Geriatric Use under Cautions.)

Gender or Race

Dosage adjustment not required.

Cautions for Eslicarbazepine

Contraindications

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 Clcr <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 (Clcr <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

Drug

Interaction

Comments

Carbamazepine

Decreased AUC of eslicarbazepine by 25–47%; pharmacokinetics of carbamazepine not substantially affected

Increased risk of adverse neurologic effects (e.g., diplopia, dizziness); increased risk of hyponatremia

Adjust dosage of eslicarbazepine acetate and/or carbamazepine based on efficacy and tolerability; consider monitoring sodium and chloride concentrations

Clobazam

Eslicarbazepine exposure generally not substantially affected

Possible increased clobazam exposure; however, clearance of clobazam not affected in a pharmacokinetic analysis

No dosage adjustments necessary

Contraceptives, oral

Dosage-dependent decreases in ethinyl estradiol and levonorgestrel concentrations; possible reduced contraceptive efficacy

Additional or nonhormonal methods of birth control recommended during eslicarbazepine acetate therapy and for at least 1 menstrual cycle following discontinuance

Desmopressin

Increased risk of hyponatremia

Consider monitoring sodium and chloride concentrations

Digoxin

No clinically important effect on digoxin AUC

Digoxin dosage adjustment not necessary

Diuretics

Increased risk of hyponatremia

Consider monitoring sodium and chloride concentrations

Gabapentin

Eslicarbazepine exposure generally not substantially affected

Systemic exposure of gabapentin not affected by eslicarbazepine acetate

No dosage adjustments necessary

HMG-CoA reductase inhibitors (statins)

Rosuvastatin: Decreased AUC of rosuvastatin by 36–39%

Simvastatin: Decreased AUC of simvastatin (a CYP3A4 substrate) by 41–61%

Adjust dosage of rosuvastatin or simvastatin if clinically significant change in serum lipids observed

Lamotrigine

Eslicarbazepine exposure generally not substantially affected

Systemic exposure of lamotrigine not affected by eslicarbazepine acetate

No dosage adjustments necessary

Levetiracetam

Eslicarbazepine exposure generally not substantially affected

Systemic exposure of levetiracetam not affected by eslicarbazepine acetate

No dosage adjustments necessary

Metformin

No clinically important effect on metformin exposure

Metformin dosage adjustment not necessary

Omeprazole

Possible increased exposure of omeprazole (a CYP2C19 substrate)

Oxcarbazepine

Eslicarbazepine is the S-enantiomer of the main active metabolite of oxcarbazepine; possible increased risk of adverse effects

Avoid concurrent use

Phenobarbital

Possible decreased eslicarbazepine exposure; phenobarbital exposure not affected

Increased eslicarbazepine acetate dosage may be necessary

Phenytoin

Possible decreased eslicarbazepine exposure and increased phenytoin exposure

Increased eslicarbazepine acetate dosage may be necessary

Monitor serum phenytoin concentrations; adjust phenytoin dosage based on clinical response and therapeutic drug monitoring

Primidone

Possible decreased eslicarbazepine exposure

Increased eslicarbazepine acetate dosage may be necessary

Topiramate

Systemic exposure of eslicarbazepine not substantially affected

Topiramate exposure decreased by 18%

No dosage adjustments necessary

Valproate

Eslicarbazepine exposure generally not substantially affected

Systemic exposure of valproate not affected by eslicarbazepine acetate

No dosage adjustments necessary

Warfarin

Decreased AUC of S-warfarin by 23%; no effect on R-warfarin

Monitor INR

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 Clcr >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 Clcr.

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

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

Eslicarbazepine Acetate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

200 mg

Aptiom (scored)

Sunovion

400 mg

Aptiom

Sunovion

600 mg

Aptiom (scored)

Sunovion

800 mg

Aptiom (scored)

Sunovion

AHFS DI Essentials™. © Copyright 2024, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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