AHFS Class:

• Ion Channel Inhibition Agents 28:12.24

Generic Name(s):

• Eslicarbazepine

• Eslicarbazepine Acetate

Eslicarbazepine acetate, a dibenz[ b , f ]azepine-5-carboxamide derivative, is an anticonvulsant.1,4,6,7,9 Eslicarbazepine acetate is a prodrug that is metabolized to eslicarbazepine ( S -licarbazepine), the major active metabolite of oxcarbazepine.1,4,6,7,9,27

Seizure Disorders

Partial Seizures

Eslicarbazepine acetate is used orally in combination with other anticonvulsant agents in the management of partial-onset seizures in adults.1,2,3,4

Efficacy of eslicarbazepine acetate as adjunctive therapy for partial-onset seizures was established in 3 multicenter, randomized, double-blind, placebo-controlled studies of similar design in adult patients with refractory partial-onset seizures (with or without secondary generalization).1,2,3,4 All 3 studies consisted of an 8-week baseline period followed by a double-blind treatment period consisting of a 2-week titration period and a subsequent 12-week maintenance period.1,2,3,4 Studies 1 and 2 compared eslicarbazepine acetate dosages of 400 mg, 800 mg, and 1.2 g once daily with placebo, and study 3 compared eslicarbazepine acetate dosages of 800 mg and 1.2 g once daily with placebo.1,2,3,4 During the 8-week baseline period, patients who were receiving stable dosages of 1-3 anticonvulsants for at least 2 months prior to screening and who had an average of 4 or more partial-onset seizures per 28 days with no seizure-free period exceeding 21 days were randomized to the double-blind treatment period.1,2,3,4 The median duration of epilepsy in the patients in these studies was 19 years and the median baseline seizure frequency was 8 seizures per 28 days; 69% of patients were receiving 2 concomitantly administered anticonvulsants and 28% were receiving one concomitant anticonvulsant.1 The most commonly used anticonvulsants were carbamazepine (50%), lamotrigine (24%), valproate (21%), and levetiracetam (18%); patients receiving oxcarbazepine or felbamate were excluded from the studies.1,2,4

Efficacy of eslicarbazepine acetate was evaluated principally by the standardized seizure frequency over 28 days during the maintenance phase (primary efficacy endpoint) as well as the secondary endpoint of percent reduction in seizure frequency from baseline to the end of the treatment period, based on self-reported patient diaries.1,2,3,4,5 Eslicarbazepine acetate 400 mg daily was assessed and not found to be substantially more effective than placebo in reducing seizures in studies 1 and 2.1 The 800-mg daily dosage of the drug substantially reduced seizure frequency compared with placebo in studies 1 and 2, but not in study 3.1,2,5 In all 3 studies, eslicarbazepine acetate 1.2 g daily was more effective than placebo in reducing seizure frequency.1,2,5

Results of longer-term, open-label extensions of studies 1 and 2 indicate that reductions in seizure frequency are maintained in patients who continue to receive eslicarbazepine acetate for at least 1 year.20,21 Approximately 69-77% of the patients enrolled in these extension studies completed one year of treatment with the drug; the median dosage was 800 mg once daily in both studies.20,21 Eslicarbazepine acetate therapy was generally well tolerated, and improvements in quality of life and depressive symptoms were observed in both long-term studies.20,21

Eslicarbazepine is commercially available as the acetate salt, which is rapidly and almost completely reduced by esterases in the liver to the active S -enantiomer, which is called S -licarbazepine or eslicarbazepine.1,4,6,7,9,27,28,29 (See Description.) Oxcarbazepine, another anticonvulsant, also is a prodrug that is metabolized to both the S -enantiomer (active) and R -enantiomer (inactive) of licarbazepine.27,28,29 It has been suggested that the nearly complete conversion of eslicarbazepine acetate to its active metabolite, eslicarbazepine, and the drug's preferential action on the inactivated state of the ion channel potentially may result in improved tolerability (including fewer neurologic adverse effects and a reduced risk of hyponatremia) and anticonvulsant efficacy compared with oxcarbazepine.6,7,9,28,29 However, controlled comparative trials between eslicarbazepine acetate and oxcarbazepine have not been conducted to date and are needed to fully evaluate the relative efficacy and tolerability of these 2 structurally related anticonvulsants.27,28,29 The once-daily dosage regimen of eslicarbazepine acetate may help improve patient compliance over many other anticonvulsants, which require more frequent administration.28,29

Administration

Eslicarbazepine acetate tablets are administered orally once daily without regard to food.1 The tablets may be swallowed whole or crushed.1

If therapy is to be discontinued, eslicarbazepine acetate should be withdrawn gradually to minimize the potential for increased seizure frequency and status epilepticus in patients with seizure disorders.1 (See Discontinuance of Therapy under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Patients currently receiving or beginning therapy with eslicarbazepine acetate and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.1,10,11,12 (See Suicidality Risk under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Dosage

Dosage of eslicarbazepine acetate is expressed in terms of the acetate salt.1

Partial Seizures

For adjunctive therapy of partial-onset seizures in adults, the recommended initial dosage of eslicarbazepine acetate is 400 mg once daily.1 After 1 week, the dosage should be increased to the recommended maintenance dosage of 800 mg once daily.1 Some patients may benefit from the maximum recommended dosage of 1.2 g once daily; however, this dosage is associated with an increased incidence of adverse effects.1,2 The maximum dosage of 1.2 g once daily should only be initiated after the patient has tolerated 800 mg once daily for at least 1 week.1 For some patients, eslicarbazepine acetate therapy may be initiated at 800 mg once daily if the need for additional seizure reduction outweighs the risk of increased adverse effects during initiation of therapy.1,4

Concurrent Use of Other Anticonvulsants

Oxcarbazepine: Because eslicarbazepine is the S -enantiomer of the major metabolite of oxcarbazepine, eslicarbazepine acetate should not be used as adjunctive therapy with oxcarbazepine.1,6,7,8

Carbamazepine: Some adverse effects such as dizziness and diplopia occur more frequently when eslicarbazepine acetate and carbamazepine are used concurrently.1 In addition, carbamazepine reduces plasma concentrations of eslicarbazepine.1 When these drugs are used concurrently, the dosages of eslicarbazepine acetate and/or carbamazepine may require adjustment based on efficacy and tolerability.1 (See Drug Interactions: Anticonvulsants.)

Other cytochrome P-450 (CYP) enzyme-inducing anticonvulsant agents (e.g., phenobarbital, phenytoin, primidone): Higher dosages of eslicarbazepine acetate may be necessary during concurrent therapy.1 (See Drug Interactions: Anticonvulsants.)

Special Populations

In patients with moderate or severe renal impairment (creatinine clearance less than 50 mL/minute), eslicarbazepine acetate therapy should be initiated at a dosage of 200 mg once daily.1 After 2 weeks, the dosage should be increased to the recommended maintenance dosage of 400 mg once daily.1 Some patients may benefit from the maximum recommended maintenance dosage of 600 mg once daily.1 No dosage adjustment is necessary for patients with mild renal impairment.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustment is not necessary in patients with mild or moderate hepatic impairment.1 Eslicarbazepine acetate has not been systematically evaluated in patients with severe hepatic impairment; use in such patients is not recommended.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Routine dosage adjustment is not necessary in geriatric patients based on age alone if their creatinine clearance is 50 mL/minute or higher; however, dosage adjustment is necessary in geriatric patients with a creatinine clearance of less than 50 mL/minute.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

No dosage adjustments are required based on gender or race.1

Contraindications

Known hypersensitivity to eslicarbazepine acetate or oxcarbazepine.1 (See Sensitivity Reactions under Cautions: Warnings/Precautions.)

Warnings/Precautions

Sensitivity Reactions

Serious Dermatologic Reactions

Serious dermatologic reactions, including Stevens-Johnson syndrome (SJS), have been reported in patients receiving 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 The incidence of these reactions associated with oxcarbazepine use exceeds the rate in the general population by threefold to tenfold.1,13

The manufacturer of eslicarbazepine acetate states that risk factors for the development of serious dermatologic reactions with the drug have not been identified to date.1 However, patients carrying the human leukocyte antigen (HLA) B*1502 allele are known to be at increased risk of developing SJS and TEN when receiving carbamazepine.13,15,16,18 The HLA-B*1502 allele also may increase the risk for SJS and TEN in patients receiving oxcarbazepine, which is structurally similar to carbamazepine.13 For further information on the risk of serious dermatologic reactions associated with the HLA-B*1502 allele, see Cautions: Dermatologic and Sensitivity Reactions, in Carbamazepine 28:12.92. The manufacturer of eslicarbazepine acetate currently makes no recommendations regarding genetic evaluation of patients receiving therapy with the drug.1

Patients receiving eslicarbazepine acetate should be monitored for dermatologic reactions.1 If a patient develops a dermatologic reaction during therapy, the drug should be discontinued unless the reaction is clearly not drug related.1 The manufacturer states that eslicarbazepine acetate should not be used in patients who developed a previous dermatologic reaction to either oxcarbazepine or eslicarbazepine acetate.1 (See Contraindications.)

Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan Hypersensitivity

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients receiving eslicarbazepine acetate.1 DRESS may be fatal or life-threatening and typically, but not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement (including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection).1 Eosinophilia is often present in patients with DRESS.1 Because this disorder is variable in its expression, clinicians should be aware that other organ systems may be involved.1 In addition, early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in some cases even when rash is not evident.1

Patients receiving eslicarbazepine acetate should be monitored for possible hypersensitivity reactions.1 If signs and symptoms associated with DRESS occur during therapy with the drug, the patient should be immediately evaluated.1 Eslicarbazepine acetate should be discontinued and not resumed if an alternative etiology for the signs and symptoms cannot be established.1 In addition, eslicarbazepine acetate should not be used in patients with a prior DRESS reaction to either oxcarbazepine or eslicarbazepine acetate.1 (See Contraindications.)

Anaphylactic Reactions and Angioedema

Rare cases of anaphylaxis and angioedema have been reported in patients receiving eslicarbazepine acetate.1 Anaphylaxis and angioedema associated with laryngeal edema can be fatal.1 Patients receiving eslicarbazepine acetate should be monitored for possible hypersensitivity reactions (e.g., breathing difficulties, swelling).1 If such reactions occur, the drug should be discontinued if another cause cannot be established.1 In addition, eslicarbazepine acetate should not be used in patients who experienced a prior anaphylactic-type reaction to either oxcarbazepine or eslicarbazepine acetate.1 (See Contraindications.)

Other Warnings and Precautions

Suicidality Risk

Suicidal behavior and ideation have been reported in patients receiving anticonvulsants.1,10,11,12 The US Food and Drug Administration (FDA) has alerted healthcare professionals about an increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants compared with placebo.1,10,11,12 The analysis of suicidality reports from placebo-controlled studies involving 11 anticonvulsants (i.e., carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).1,10,11,12 This increased suicidality risk was observed as early as 1 week after beginning therapy and continued through 24 weeks.1,10,11 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1,10

Based on the current analysis of the available data, the FDA recommends that clinicians inform patients, their families, and caregivers of the potential for an increased risk of suicidality with anticonvulsant therapy and that all patients currently receiving or beginning therapy with any anticonvulsant be monitored closely for notable changes that may indicate the emergence or worsening of suicidal thoughts or behavior or depression.1,10,11,12 Symptoms such as anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality.1,10

Clinicians who prescribe eslicarbazepine acetate or any other anticonvulsant should balance the risk of suicidality with the clinical need for the drug and the risk associated with untreated illness.1,10 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.1,12 If suicidal thoughts or behaviors emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.1,12 (See Advice to Patients.)

Hyponatremia

Clinically important hyponatremia (i.e., serum sodium concentrations less than 125 mEq/L) can develop in eslicarbazepine acetate-treated patients.1,2 In controlled epilepsy trials, serum sodium concentrations less than 125 mEq/L were reported at least once in 1 and 1.5% of patients receiving eslicarbazepine acetate 800 mg and 1.2 g daily, respectively; 5.1% of patients receiving the drug experienced decreases in sodium concentrations exceeding 10 mEq/L.1,2 Hyponatremia is dose related and generally appears during the first 8 weeks of eslicarbazepine therapy, possibly as early as after 3 days.1 Serious, life-threatening complications, which necessitated hospitalization and drug discontinuance, were associated with the hyponatremia in some patients.1 Concurrent hypochloremia also was present.1

The manufacturer states that monitoring of serum sodium and chloride concentrations should be considered during maintenance therapy with eslicarbazepine acetate, particularly in patients concurrently receiving other drugs known to decrease serum sodium concentrations (e.g., carbamazepine, desmopressin, diuretics).1,25 The manufacturer also states that serum sodium and chloride concentrations should be measured if patients receiving eslicarbazepine acetate 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 In patients who develop hyponatremia during therapy, the dosage of eslicarbazepine acetate may need to be reduced or the drug discontinued.1

Neurologic Effects

Eslicarbazepine acetate can cause a variety of adverse neurologic effects, including 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).1 These effects are all dose related and there is an increased risk of some of these adverse effects (including dizziness, disturbances in gait or coordination, and visual changes) during the dosage titration phase (compared with the maintenance phase).1 In addition, patients 60 years of age or older may be at increased risk of some of these adverse effects (including dizziness, disturbances in gait or coordination, and visual changes) compared with younger adults.1

In controlled studies in patients with epilepsy, dizziness and disturbances in gait and coordination were reported in 26 and 38% of patients receiving eslicarbazepine acetate dosages of 800 mg and 1.2 g daily, respectively, compared with 12% of those receiving placebo.1 Nausea and vomiting also occurred with these adverse effects.1 Somnolence and fatigue-related adverse effects (e.g., asthenia, malaise, hypersomnia, sedation, lethargy) occurred in 16 and 28% of patients receiving eslicarbazepine acetate dosages of 800 mg and 1.2 g daily, respectively, and in 13% of those receiving placebo.1 Cognitive dysfunction-related adverse effects were reported in 4 and 7% of patients receiving eslicarbazepine acetate 800 mg and 1.2 g daily, respectively, compared with 1% of those receiving placebo.1 Visual disturbances were reported in 16% of patients receiving eslicarbazepine acetate compared with 6% of those receiving placebo.1

The incidence of dizziness and diplopia was greater when eslicarbazepine acetate was used concomitantly with carbamazepine than when it was used without carbamazepine; therefore, dosage adjustment of eslicarbazepine acetate and/or carbamazepine should be considered during concurrent administration of the drugs.1 (See Partial Seizures under Dosage and Administration: Dosage and also see Drug Interactions: Anticonvulsants.)

Patients should be cautioned about the possibility of adverse neurologic effects with eslicarbazepine acetate therapy and advised not to engage in hazardous activities requiring mental alertness and coordination (e.g., operating a motor vehicle or other dangerous machinery) until the effects of the drug are known.1 (See Advice to Patients.)

Discontinuance of Therapy

As with all anticonvulsant agents, there is a potential for increased seizure frequency and status epilepticus when eslicarbazepine acetate therapy is withdrawn abruptly.1 The dosage of eslicarbazepine acetate should be reduced gradually and abrupt discontinuance should be avoided when discontinuing therapy with the drug.1

Drug-induced Liver Injury

Adverse hepatic effects, ranging from mild to moderate elevations in transaminases (over 3 times the upper limit of normal) to rare cases with concomitant elevations of total bilirubin (over 2 times the upper limit of normal) have been reported with eslicarbazepine acetate.1 The manufacturer recommends baseline evaluation of liver function tests.1 The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury.1 Eslicarbazepine acetate should be discontinued if jaundice or other evidence of substantial liver injury (i.e., laboratory evidence) is observed.1

Abnormal Thyroid Function Tests

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

Specific Populations

Pregnancy

Category C.1 (See Users Guide.)

The North American Antiepileptic Drug (NAAED) Pregnancy Registry may be contacted at 888-233-2334 (for patients); NAAED registry information also is available on the website [Web].1

Eslicarbazepine acetate produced developmental toxicity, including teratogenicity, embryolethality, and fetal growth retardation, when administered orally to pregnant animals in clinically relevant dosages.1

Lactation

Eslicarbazepine is distributed into human milk.1 Because of the potential for serious adverse reactions to eslicarbazepine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

Pediatric Use

The manufacturer states that the safety and efficacy of eslicarbazepine acetate have not been established in pediatric patients younger than 18 years of a the drug is not FDA-labeled for use in pediatric patients.1,23 However, the pharmacokinetics, efficacy, and tolerability of eslicarbazepine acetate have been evaluated in 29 pediatric patients (2-17 years of age) with refractory partial-onset seizures in an open study.22,23 The patients were divided into the following age groups: 2-6 years of age, 7-11 years of age, and 12-17 years of age.22,23 Peak plasma concentrations of eslicarbazepine were dose-dependent, were similar between age groups following identical dosage based on weight, and occurred within 0.5-3 hours in these pediatric patients.22,23 Area under the plasma concentration-time curve (AUC) was age-dependent due to faster plasma clearance of eslicarbazepine in the younger children compared with the older children.22,23 A dose-dependent decrease in relative seizure frequency was observed in the younger children (2-6 years of age) and adolescent (12-17 years of age) treatment groups, but not in the older children (7-11 years of age).22,23 Eslicarbazepine therapy was generally well tolerated in the pediatric patients in this study.22,23

Geriatric Use

Experience with eslicarbazepine acetate in patients 65 years of age and older is insufficient to establish efficacy in this population.1

Patients 60 years of age and older appear to be at increased risk of adverse neurologic effects associated with eslicarbazepine acetate therapy (including dizziness, disturbances in gait or coordination, and visual changes) compared with younger adults.1 (See Neurologic Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

In a study comparing single- and multiple-dose pharmacokinetics of eslicarbazepine acetate in geriatric individuals with a creatinine clearance greater than 60 mL/minute and younger healthy adults (18-40 years of age), the pharmacokinetic profile of the drug was similar between the 2 age groups.1,7 Although the pharmacokinetics of eslicarbazepine do not appear to be affected by age, the manufacturer states that dosage selection in geriatric patients should take into consideration the greater frequency of renal impairment and other concomitant medical conditions and medications in this population.1 Dosage adjustment is necessary in geriatric patients with a creatinine clearance of less than 50 mL/minute.1

Hepatic Impairment

Moderate hepatic impairment does not affect the pharmacokinetics of eslicarbazepine acetate; therefore, dosage adjustment is not necessary in patients with mild or moderate hepatic impairment.1

The pharmacokinetics of eslicarbazepine acetate have not been studied in patients with severe hepatic impairment, and use of the drug in such patients is not recommended.1

Renal Impairment

Clearance of eslicarbazepine is reduced in patients with renal impairment and is correlated with creatinine clearance.1 In a pharmacokinetic study, systemic exposure of eslicarbazepine following a single 800-mg dose of eslicarbazepine acetate was increased by 62% in patients with mild renal impairment and by 2 and 2.5 times in patients with moderate and severe renal impairment, respectively.1 Dosage adjustment is recommended in patients with a creatinine clearance of less than 50 mL/minute.1 (See Dosage and Administration: Special Populations.)

In patients with end-stage renal disease, repeated hemodialysis removes eslicarbazepine and other metabolites from the systemic circulation.1

Common Adverse Effects

Adverse effects reported in at least 4% of patients with partial-onset seizures receiving eslicarbazepine acetate in controlled clinical trials and at least 2% more frequently than placebo include 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 and tremor.1

Eslicarbazepine is a moderate inhibitor of cytochrome P-450 (CYP) isoenzyme 2C19.1,8 In vivo studies suggest that eslicarbazepine can induce CYP3A4, leading to clinically relevant drug interactions with substrates of this isoenzyme.1 The drug does not appear to inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4, nor to induce CYP1A2 or phase II hepatic enzymes involved in glucuronidation or sulfation.1,8 A mild activation of uridine diphosphate-glucuronosyltransferase (UGT) 1A1-mediated glucuronidation has been observed in vitro.1 Autoinduction of eslicarbazepine metabolism has not been observed.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Concomitant use of eslicarbazepine acetate with CYP enzyme-inducing anticonvulsants may decrease systemic exposure to eslicarbazepine.1,8

Clinically relevant pharmacokinetic interactions also are possible when eslicarbazepine acetate is used concomitantly with CYP3A4 substrates (e.g., oral contraceptives, simvastatin); decreased plasma concentrations of the CYP3A4 substrate may occur and a higher dosage of the substrate may be necessary.1,27

Because eslicarbazepine acetate can inhibit CYP2C19, increased plasma concentrations of drugs that are metabolized by this isoenzyme (e.g., clobazam, omeprazole, phenytoin) also potentially may occur during concurrent administration.1,27 (See Drug Interactions: Anticonvulsants and also see Drug Interactions: Omeprazole.)

Anticonvulsants

Carbamazepine

Concomitant administration of eslicarbazepine acetate and carbamazepine decreased the area under the plasma concentration-time curve (AUC) of eslicarbazepine by 25-47%.1,8,19 Carbamazepine pharmacokinetics were not substantially affected by eslicarbazepine acetate.1,8,19

In clinical trials, combined use of eslicarbazepine acetate and carbamazepine was associated with an increased incidence of adverse effects (e.g., dizziness, diplopia) compared with combined use of eslicarbazepine acetate and other anticonvulsants.1,8,19 The risk of hyponatremia also may be increased during combined use of these drugs.1,25 (See Hyponatremia and also see Neurologic Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

During concurrent use, dosages of eslicarbazepine acetate and/or carbamazepine may require adjustment based on efficacy and tolerability.1 (See Dosage and Administration: Dosage.) In addition, monitoring of serum sodium and chloride concentrations for possible hyponatremia should be considered.1,25

Clobazam

Systemic exposure to eslicarbazepine is not substantially affected by concomitant administration of clobazam.8 There is a potential for increased plasma concentrations of clobazam, a substrate of CYP2C19, when used concomitantly with eslicarbazepine.1,19 However, in a pooled population pharmacokinetic analysis of eslicarbazepine acetate given concomitantly with other anticonvulsants, eslicarbazepine acetate did not substantially affect the clearance of clobazam.8

Oxcarbazepine

Because eslicarbazepine is the S -enantiomer of the major metabolite of oxcarbazepine, the manufacturer states that eslicarbazepine acetate should not be used as adjunctive therapy with oxcarbazepine.1,6,7,8

Phenobarbital

No dedicated drug-drug interaction studies evaluating eslicarbazepine acetate and phenobarbital have been conducted.19 In population analyses, concomitant administration of CYP enzyme-inducing anticonvulsants (e.g., phenytoin, primidone) decreased the AUC of eslicarbazepine.1,19 Phenobarbital exposure was not substantially affected by eslicarbazepine acetate.1,8,19 The manufacturer states that higher dosages of eslicarbazepine acetate may be necessary in patients receiving phenobarbital.1

Phenytoin

In healthy individuals, concomitant administration of eslicarbazepine acetate and phenytoin resulted in decreased exposure (31-33%) to eslicarbazepine and increased exposure (31-35%) to phenytoin.1,8,19 The manufacturer states that patients receiving these anticonvulsants in combination may require a higher dosage of eslicarbazepine acetate.1,8,19 In addition, serum phenytoin concentrations should be monitored in patients receiving eslicarbazepine acetate; dosage adjustment of phenytoin may be necessary based on clinical response and therapeutic drug monitoring.1,8,19 (See Dosage and Administration: Dosage.)

Primidone

In population analyses, concomitant administration of CYP-inducing anticonvulsants (e.g., phenytoin, primidone) decreased the AUC of eslicarbazepine.1,19 The manufacturer states that higher dosages of eslicarbazepine acetate may be necessary in patients receiving primidone.1

Topiramate

In a pharmacokinetic study, systemic exposure of eslicarbazepine acetate (1.2 g once daily) was not substantially affected by concomitant administration of topiramate (200 mg once daily) in healthy individuals.1,24 Topiramate exposure decreased by 18%.1,8,19,24 No dosage adjustments are necessary when these anticonvulsants are used concurrently.1,8,19,24

Other Anticonvulsants

Pharmacokinetic studies indicate that systemic exposure to eslicarbazepine is not substantially affected by concomitant administration of gabapentin, lamotrigine, levetiracetam, or valproate.1 In addition, systemic exposure of these anticonvulsants is not substantially affected by concomitant administration of eslicarbazepine acetate.1,8 Dosage adjustments are therefore not necessary during concurrent use of eslicarbazepine acetate and these anticonvulsants.1,8,19

Digoxin

In healthy individuals, concomitant administration of eslicarbazepine acetate (1.2 g daily for 8 days) and digoxin had no clinically important effect on the AUC of digoxin.1,8,19 Digoxin dosage adjustment is not necessary in patients concurrently receiving eslicarbazepine acetate.1,19

Drugs associated with Hyponatremia

Because of the increased risk of hyponatremia in eslicarbazepine acetate-treated patients concurrently receiving other drugs associated with hyponatremia (e.g., carbamazepine, desmopressin, diuretics), monitoring of serum sodium and chloride concentrations should be considered in such patients.1,25 (See Hyponatremia under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

HMG-CoA Reductase Inhibitors (Statins)

Rosuvastatin

In healthy individuals, concomitant administration of eslicarbazepine acetate (1.2 g daily) and rosuvastatin reduced systemic exposure of rosuvastatin by an average of 36-39%.1,25 Dosage adjustment of rosuvastatin may be necessary during concurrent use if a clinically significant change in serum lipids is observed.1

Simvastatin

In healthy individuals, concomitant administration of eslicarbazepine acetate (800 mg daily) and a single 80-mg dose of simvastatin (a CYP3A4 substrate) reduced systemic exposure of simvastatin by 41-61%.1,8,25,26 Dosage adjustment of simvastatin may be necessary during concurrent use if a clinically significant change in serum lipids is observed.1,8,26

Metformin

In healthy individuals, concomitant administration of eslicarbazepine acetate (1.2 g daily for 6 days) and metformin (single 850-mg dose) did not have a clinically important effect on the AUC of metformin.1,8 Metformin dosage adjustment is not necessary in patients receiving eslicarbazepine acetate concurrently.1

Omeprazole

Increased plasma concentrations of omeprazole (a CYP2C19 substrate) may occur in patients concurrently receiving eslicarbazepine acetate.1

Oral Contraceptives

In healthy females, concomitant use of eslicarbazepine acetate (800 mg daily) and an oral contraceptive containing ethinyl estradiol and levonorgestrel decreased systemic exposure of estradiol by 30%; levonorgestrel exposure was not affected.1,8 The enzyme-inducing effect of eslicarbazepine acetate on metabolism of oral contraceptives appears to be dose dependent; at daily dosages of 1.2 g, systemic exposure of levonorgestrel and estradiol decreased by 42 and 37%, respectively.1,8

To ensure contraceptive reliability, the manufacturer recommends that women receiving oral contraceptives use additional or alternative nonhormonal forms of contraception during eslicarbazepine acetate therapy and for at least one menstrual cycle following discontinuance of the drug.1,8 (See Advice to Patients.)

Warfarin

Concomitant administration of eslicarbazepine acetate (1.2 g daily) and warfarin decreased the AUC of the S -enantiomer of warfarin by 23%, but did not have a substantial effect on the AUC of R -warfarin.1,8 The manufacturer recommends clinical monitoring of INR in patients concurrently receiving warfarin.1,8

Description

Eslicarbazepine acetate, a prodrug of eslicarbazepine, is a dibenzazepine voltage-gated sodium channel (VGSC) blocker; the drug is an anticonvulsant.1,4,6,7,9,27 Eslicarbazepine acetate is structurally similar to 2 other dibenzazepine anticonvulsants, carbamazepine and oxcarbazepine.6,7,8,29 Eslicarbazepine is the S -enantiomer of racemic licarbazepine, which is the active, 10-monohydroxy metabolite of oxcarbazepine (MHD).6,7,8,29 Although the exact mechanism by which eslicarbazepine acetate exerts its anticonvulsant effects has not been fully elucidated, the drug, like carbamazepine and oxcarbazepine, is thought to selectively reduce excitability of rapidly firing neurons by inhibiting voltage-gated sodium channels.1,4,6,7,9,27 Eslicarbazepine appears to preferentially target the inactivated state of the ion channel and exhibits a higher binding affinity for the inactivated state than for the resting state, preventing its return to the active state and thereby reducing repetitive neuronal firing.6,7,9

Following oral administration, eslicarbazepine acetate is rapidly and extensively metabolized by hydrolytic first-pass metabolism to eslicarbazepine; plasma concentrations of the parent drug remain mostly undetectable.1,4,6,7,8 Peak plasma concentrations of eslicarbazepine occur 1-4 hours following oral administration of the drug.1,8 Food does not affect the pharmacokinetics of eslicarbazepine acetate.1,8 The drug exhibits linear and dose-proportional pharmacokinetics at recommended dosages.1 Steady-state concentrations of eslicarbazepine are attained 4-5 days after once-daily dosing.1 Protein binding of eslicarbazepine is relatively low (less than 40%) and independent of plasma concentration.1 Eslicarbazepine accounts for 91% of systemic exposure; systemic exposure to the 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.1,6,8 Autoinduction of metabolism has not been observed with the drug.1 Eslicarbazepine and other metabolites are primarily eliminated by renal excretion in the unchanged and glucuronide conjugate forms; over 90% of an eslicarbazepine acetate dose is recovered in urine as unchanged eslicarbazepine (approximately two-thirds) or as glucuronide conjugates (approximately one-third).1 The renal clearance of eslicarbazepine is substantially lower than the glomerular filtration rate in healthy individuals with normal renal function, suggesting that renal tubular reabsorption occurs.1 The elimination half-life of eslicarbazepine is 13-20 hours in patients with epilepsy.1 Hemodialysis partially clears eslicarbazepine from the systemic circulation in patients with end-stage renal disease.1

Advice to Patients

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

Importance of taking eslicarbazepine acetate only as prescribed.1

Importance of patients, family members, and caregivers being aware that anticonvulsants, including eslicarbazepine acetate, may increase the risk of having suicidal thoughts or actions in a very small number of people (about 1 in 500).1,10,12 Advise patients, family members, and caregivers to pay close attention to any day-to-day changes in mood, behavior, and actions; these changes can happen very quickly.1,10 They should also be aware of common warning signs that may signal suicide risk (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 Advise patients, family members, and caregivers to contact the responsible clinician immediately if these or any new and worrisome behaviors occur.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 with eslicarbazepine acetate.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 with eslicarbazepine acetate therapy.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 that eslicarbazepine acetate can cause 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 eslicarbazepine acetate 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 North American Antiepileptic Drug Pregnancy Registry.1 (See Pregnancy under Warnings/Precautions: Specific Populations, in 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.1

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

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.

1. Sunovion Pharmaceuticals Inc. Aptiom^® (eslicarbazepine acetate) tablets prescribing information. Marlborough, MA; 2013 Nov.

2. Elger C, Halász P, Maia J et al. Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase III study. Epilepsia . 2009; 50:454-63. [PubMed 19243424]

3. Ben-Menachem E, Gabbai AA, Hufnagel A et al. Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res . 2010; 89:278-85. [PubMed 20299189]

4. Gil-Nagel A, Lopes-Lima J, Almeida L et al. Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures. Acta Neurol Scand . 2009; 120:281-7. [PubMed 19832771]

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9. Bonifácio MJ, Sheridan RD, Parada A et al. Interaction of the novel anticonvulsant, BIA 2-093, with voltage-gated sodium channels: comparison with carbamazepine. Epilepsia . 2001; 42:600-8. [PubMed 11380566]

10. US Food and Drug Administration. FDA Alert: Information for healthcare professionals: suicidal behavior and ideation and antiepileptic drugs. Rockville, MD; 2008 Jan 31; updated 2008 Dec 16. From the FDA website. [Web]

11. US Food and Drug Administration. FDA News: FDA alerts health care providers to risk of suicidal thoughts and behavior with antiepileptic medications. Rockville, MD; 2008 Jan 31. From the FDA website. [Web]

12. US Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs: update 5/5/2009. Rockville, MD; 2009 May 5. From the FDA website. Accessed 2012 May 4. [Web]

13. Novartis Pharmaceuticals Corporation. Trileptal^® (oxcarbazepine) film-coated tablets and oral suspension prescribing information. East Hanover, NJ; 2014 Jul.

15. US Food and Drug Administration. Information for healthcare professionals: dangerous or even fatal skin reactions - carbamazepine (marketed as Carbatrol, Equetro, Tegretol, and generics). Rockville, MD; 2007 Dec 12. From the FDA website. [Web]

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18. Tangamornsuksan W, Chaiyakunapruk N, Somkrua R et al. Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol . 2013; 149:1025-32. [PubMed 23884208]

19. Sunovion Pharmaceuticals Inc. Aptiom^® (eslicarbazepine acetate) - drug interactions evaluations. Marlborough, MA; 2014.

20. Halász P, Cramer JA, Hodoba D et al. Long-term efficacy and safety of eslicarbazepine acetate: results of a 1-year open-label extension study in partial-onset seizures in adults with epilepsy. Epilepsia . 2010; 51:1963-9. [PubMed 20662896]

21. Hufnagel A, Ben-Menachem E, Gabbai AA et al. Long-term safety and efficacy of eslicarbazepine acetate as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy: results of a 1-year open-label extension study. Epilepsy Res . 2013; 103:262-9. [PubMed 22871333]

22. Almeida L, Minciu I, Nunes T et al. Pharmacokinetics, efficacy, and tolerability of eslicarbazepine acetate in children and adolescents with epilepsy. J Clin Pharmacol . 2008; 48:966-77. [PubMed 18508949]

23. Sunovion Pharmaceuticals Inc. Aptiom^® (eslicarbazepine acetate) - data relating to pediatric patients. Marlborough, MA; 2014.

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