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Uses

Seizure Disorders

Partial Seizures

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

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). 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. 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. 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. 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. 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.

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. 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. 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. In all 3 studies, eslicarbazepine acetate 1.2 g daily was more effective than placebo in reducing seizure frequency.

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. 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. Eslicarbazepine acetate therapy was generally well tolerated, and improvements in quality of life and depressive symptoms were observed in both long-term studies.

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.(See Description.) Oxcarbazepine, another anticonvulsant, also is a prodrug that is metabolized to both the S-enantiomer (active) and R-enantiomer (inactive) of licarbazepine. 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. 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. The once-daily dosage regimen of eslicarbazepine acetate may help improve patient compliance over many other anticonvulsants, which require more frequent administration.

Dosage and Administration

Administration

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

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.(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.(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.

Partial Seizures

For adjunctive therapy of partial-onset seizures in adults, the recommended initial dosage of eslicarbazepine acetate is 400 mg once daily. After 1 week, the dosage should be increased to the recommended maintenance dosage of 800 mg once daily. 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. 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. 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.

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.

Carbamazepine: Some adverse effects such as dizziness and diplopia occur more frequently when eslicarbazepine acetate and carbamazepine are used concurrently. In addition, carbamazepine reduces plasma concentrations of eslicarbazepine. When these drugs are used concurrently, the dosages of eslicarbazepine acetate and/or carbamazepine may require adjustment based on efficacy and tolerability.(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.(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. After 2 weeks, the dosage should be increased to the recommended maintenance dosage of 400 mg once daily. Some patients may benefit from the maximum recommended maintenance dosage of 600 mg once daily. No dosage adjustment is necessary for patients with mild renal impairment.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

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

No dosage adjustments are required based on gender or race.

Cautions

Contraindications

Known hypersensitivity to eslicarbazepine acetate or oxcarbazepine.(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. 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. The incidence of these reactions associated with oxcarbazepine use exceeds the rate in the general population by threefold to tenfold.

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. 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. The HLA-B*1502 allele also may increase the risk for SJS and TEN in patients receiving oxcarbazepine, which is structurally similar to carbamazepine. The manufacturer of eslicarbazepine acetate currently makes no recommendations regarding genetic evaluation of patients receiving therapy with the drug.

Patients receiving eslicarbazepine acetate should be monitored for dermatologic reactions. If a patient develops a dermatologic reaction during therapy, the drug should be discontinued unless the reaction is clearly not drug related. The manufacturer states that eslicarbazepine acetate should not be used in patients who developed a previous dermatologic reaction to either oxcarbazepine or eslicarbazepine acetate.(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. 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). Eosinophilia is often present in patients with DRESS. Because this disorder is variable in its expression, clinicians should be aware that other organ systems may be involved. In addition, early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in some cases even when rash is not evident.

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

Anaphylactic Reactions and Angioedema

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

Other Warnings and Precautions

Suicidality Risk

Suicidal behavior and ideation have been reported in patients receiving anticonvulsants. 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. 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%). This increased suicidality risk was observed as early as 1 week after beginning therapy and continued through 24 weeks. 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.

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. Symptoms such as anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality.

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. 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. If suicidal thoughts or behaviors emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.(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. 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. Hyponatremia is dose related and generally appears during the first 8 weeks of eslicarbazepine therapy, possibly as early as after 3 days. Serious, life-threatening complications, which necessitated hospitalization and drug discontinuance, were associated with the hyponatremia in some patients. Concurrent hypochloremia also was present.

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). 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). In patients who develop hyponatremia during therapy, the dosage of eslicarbazepine acetate may need to be reduced or the drug discontinued.

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). 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). 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.

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. Nausea and vomiting also occurred with these adverse effects. 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. 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. Visual disturbances were reported in 16% of patients receiving eslicarbazepine acetate compared with 6% of those receiving placebo.

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.(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.(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. The dosage of eslicarbazepine acetate should be reduced gradually and abrupt discontinuance should be avoided when discontinuing therapy with the drug.

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. The manufacturer recommends baseline evaluation of liver function tests. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury. Eslicarbazepine acetate should be discontinued if jaundice or other evidence of substantial liver injury (i.e., laboratory evidence) is observed.

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. These changes were not associated with other abnormal thyroid function test results suggesting hypothyroidism. Clinical evaluation of abnormal thyroid test results in eslicarbazepine acetate-treated patients is recommended.

Specific Populations

Pregnancy

Category C.

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 http://www.aedpregnancyregistry.org.

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

Lactation

Eslicarbazepine is distributed into human milk. 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.

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 age; the drug is not FDA-labeled for use in pediatric patients. 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. 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. 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. 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. 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). Eslicarbazepine therapy was generally well tolerated in the pediatric patients in this study.

Geriatric Use

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

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.(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. 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. Dosage adjustment is necessary in geriatric patients with a creatinine clearance of less than 50 mL/minute.

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.

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.

Renal Impairment

Clearance of eslicarbazepine is reduced in patients with renal impairment and is correlated with creatinine clearance. 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. Dosage adjustment is recommended in patients with a creatinine clearance of less than 50 mL/minute.(See Dosage and Administration: Special Populations.)

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

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

Drug Interactions

Eslicarbazepine is a moderate inhibitor of cytochrome P-450 (CYP) isoenzyme 2C19. In vivo studies suggest that eslicarbazepine can induce CYP3A4, leading to clinically relevant drug interactions with substrates of this isoenzyme. 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. A mild activation of uridine diphosphate-glucuronosyltransferase (UGT) 1A1-mediated glucuronidation has been observed in vitro. Autoinduction of eslicarbazepine metabolism has not been observed.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

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

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.

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. (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%. Carbamazepine pharmacokinetics were not substantially affected by eslicarbazepine acetate.

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. The risk of hyponatremia also may be increased during combined use of these drugs. (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.(See Dosage and Administration: Dosage.) In addition, monitoring of serum sodium and chloride concentrations for possible hyponatremia should be considered.

Clobazam

Systemic exposure to eslicarbazepine is not substantially affected by concomitant administration of clobazam. There is a potential for increased plasma concentrations of clobazam, a substrate of CYP2C19, when used concomitantly with eslicarbazepine. 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.

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.

Phenobarbital

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

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. The manufacturer states that patients receiving these anticonvulsants in combination may require a higher dosage of eslicarbazepine acetate. 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.(See Dosage and Administration: Dosage.)

Primidone

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

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. Topiramate exposure decreased by 18%. No dosage adjustments are necessary when these anticonvulsants are used concurrently.

Other Anticonvulsants

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

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. Digoxin dosage adjustment is not necessary in patients concurrently receiving eslicarbazepine acetate.

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.(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%. Dosage adjustment of rosuvastatin may be necessary during concurrent use if a clinically significant change in serum lipids is observed.

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%. Dosage adjustment of simvastatin may be necessary during concurrent use if a clinically significant change in serum lipids is observed.

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. Metformin dosage adjustment is not necessary in patients receiving eslicarbazepine acetate concurrently.

Omeprazole

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

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. 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.

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.(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. The manufacturer recommends clinical monitoring of INR in patients concurrently receiving warfarin.

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