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Table of Contents
Year : 2017  |  Volume : 6  |  Issue : 6  |  Page : 245-254

Eslicarbazepine acetate: A therapeutic agent of paramount importance in acute anticonvulsant therapy

1 Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard (Hamdard University), New Delhi-110062, India
2 Department of Pharmacy, Oman Medical College, Muscat, Sultanate of Oman
3 Health Information Technology Department, Jeddah Community College, King Abdulaziz University, P.O. Box-80283, Jeddah-21589, Kingdom of Saudi Arabia

Date of Submission11-Aug-2017
Date of Decision20-Aug-2017
Date of Acceptance02-Sep-2017
Date of Web Publication27-Dec-2017

Correspondence Address:
Asif Husain
Associate Professor, Dept of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Hamdard University, New Delhi-110 062
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2221-6189.221287

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Eslicarbazepine acetate (ESL) is a new, once daily, orally administered, third generation antiepileptic drug which is indicated in the treatment of partial-onset seizures. ESL is known to exert it’s anticonvulsant effect by blocking the voltage-gated sodium channels. Several clinical trials and pharmacological studies have revealed that seizure control was better with ESL monotherapy (1 200 or 1 600 mg once daily) following a switch from other antiepileptic drugs in comparison with pseudo-placebo patients. The studies have indicated the ESL to be well tolerated and produced only mild to moderate emergent adverse events with the therapy. Being a dibenzazepine family member, structure and chemistry of ESL resembles more or less to carbamazepine and oxcarbazepine. ESL differs structurally from carbamazepine and oxcarbazepine at the 10, 11 position of dibenazepine nucleus. This molecular variation results in differences in metabolism and thus helps to prevent the formation of toxic epoxide metabolites. ESL following oral administration is rapidly metabolised to active metabolite namely S-licarbazepine which is responsible for its pharmacological activity. ESL exhibits acceptable pharmacokinetic profile and shows insignificant drug-drug interactions. In phase III clinical program, ESL was found to be efficacious and well tolerated in adult patients with partial onset seizures previously not controlled with treatment with one or two other antiepileptic drugs.

Keywords: Eslicarbazepine acetate, Partial-onset seizures, Epilepsy, Antiepileptic drugs, Drug interactions

How to cite this article:
Iram F, Khan SA, Ahmad A, Siddiqui AA, Husain A. Eslicarbazepine acetate: A therapeutic agent of paramount importance in acute anticonvulsant therapy. J Acute Dis 2017;6:245-54

How to cite this URL:
Iram F, Khan SA, Ahmad A, Siddiqui AA, Husain A. Eslicarbazepine acetate: A therapeutic agent of paramount importance in acute anticonvulsant therapy. J Acute Dis [serial online] 2017 [cited 2023 Mar 22];6:245-54. Available from: https://www.jadweb.org/text.asp?2017/6/6/245/221287

  1. Introduction Top

Over the last few decades, antiepileptic drugs (AEDs) have made a considerable impact in the treatment and management of epilepsy[1],[2]. Although, a large number of AEDs are available for the treatment of epilepsy, yet nearly 30% of patients have scanty seizure control[3]. Approximately 50 million people of all ages are affected by epilepsy worldwide[4] and it is estimated that 2.3 million adults (1%) in USA population suffers from this neurological disease. Epilepsy is a chronic non-communicable disorder of the brain which is characterized by recurring episodes of seizures. The seizures are produced due to abnormal excessive or synchronous neuronal activity in the brain[5],[6]. The disease requires a long-term treatment which necessitates the development of well tolerated novel AEDs with fewer side effects, high efficacy and having a simplified dose regimen[7],[8],[9].

Eslicarbazepine acetate (ESL) is one of the most prominent AEDs developed recently by the Bial, a Portuguese pharmaceutical company. However, in early 2009, a Japanese company Eisai bought the marketing rights in Europe[10]. In April 2009, the drug was approved for use by the European Union under the trade names Zebinix™ and Exalief™[11],[12] and as Aptiom™ in 2013 by the US Food and Drug Administration (FDA)[13].

ESL is a third generation AED whose clinical use is limited to partial-onset and generalized tonic-clonic seizures. It is a single-enantiomer member that belongs to the long-established family of the first generation dibenz[b,f]azepine AED like carbamazepine (CBZ) and second generation oxcarbazepine (OXC)[14]. ESL is a prodrug that is activated to Eslicarbazepine (S-licarbazepine), an active metabolite of OXC[15],[16],[17]. Both ESL and eslicarbazepine stabilize the inactivated state of voltage-gated sodium channels. It not only prevents the return activated state but also sustain repetitive neuronal firing[18],[19],[20]. ESL protects the development of seizures and have exhibited analgesic effects in preclinical models of epilepsy and nonclinical models of pain respectively[21],[22],[23],[24],[25].

ESL acts as a voltage-gated sodium channel blocker[26],[27],[28]. Constructively, it does not amend fast inactivation of voltage-gated sodium channel like CBZ, but alter the kinetics and voltage dependence of slow inactivation[29]. ESL is known for its improved tolerability profile as it provides a stable concentration of S-licarbazepine in CSF after administration and simplified dose regimen with a once-daily oral administration which leads to improved patient compliance[30],[31]. This review article highlights the chemical, pharmacological, pharmacodynamic and pharmacokinetic profile of ESL as a mono or adjunct therapy in epilepsy.

  2. Dosage and administration Top

2.1. Dosage for partial-onset seizures

The starting treatment dose is 400 mg orally once daily (OD) for first seven days and then recommended maintenance dose is 800-1 200 mg orally OD. Though, high maintenance dose of 1 200 mg is beneficial to some patients but leads to an increase in adverse reactions (ADRs). Generally, a dose of 1 200 mg daily is initiated for those patients who can tolerate 800 mg daily for at least one week. For some patients, treatment may be initiated at 800 mg OD, if the need for additional seizure reduction outweighs an increased risk of adverse reactions during initiation[32],[33],[34].

2.2. Dosage adjustment with other AEDs for partial-onset seizures

ESL should not be used along with OXC and CBZ as an adjunctive therapy because of the serious adverse reactions. In case of the patients taking other enzyme-inducing AEDs such as phenobarbital, phenytoin, and primidone, a higher dose adjustment is required[35],[36].

2.3. Dosage adjustment of ESL in renal impairment patients

No dose adjustment of ESL is needed if creatinine clearance is ⩾50 mL/min. In case of patients having creatinine clearance < 50 mL/min, the starting dose is 200 mg orally OD which is increased to the recommended maintenance dose of 400 mg orally OD after two weeks[33],[37].

2.4. Dosage adjustment in hepatic impairment patients

Patients suffering from mild to moderate hepatic impairment do not need a dose adjustment. No study has been conducted to investigate the use of ESL in severe hepatic impairment patients, hence in absence of clinical data, use of ESL in these patients should be avoided[28],[34],[38].

2.5. Dosage adjustment in pregnancy and lactation

There are no clinical trials which document the effect of ESL in pregnant women. However, some animal studies have suggested that ESL may be teratogenic in humans[28],[39]. ESL is excreted into breast milk and is not recommended in breast feeding mothers. CBZ is usually a choice of AED as it is compatible with breast-feeding according to The American Academy of Pediatrics (TAAP)[40].

  3. Chemistry Top

Chemically, ESL (C17H16N2O3; molecular weight 296.32) is (S)-5 carbamoyl-10, 11-dihydro-5H-dibenzo[b,f]azepin-10-yl acetate[41]. It is a white to off-white, odourless crystalline solid. ESL, CBZ and OXC share a common chemical moiety i.e. Dibenzazepine nucleus with a 5-carboxamide substituent. But ESL is structurally different at the 10, 11-position. Unlike CBZ, ESL is not metabolized into the CBZ 10, 11-epoxide, an active and potentially toxic compound. As a result, ESL has very low enzyme-inducing activity[42]. ESL has a solubility of <1 mg/mL in aqueous buffer solutions at different pH values and at physiologic conditions it remains non-ionisable. The ESL ester moiety is chemically hydrolyzed at low and high pH (1.2 and 10, respectively) to yield eslicarbazepine. Eslicarbazepine has a water solubility of 4.2 mg/mL, which is >10-fold higher than the aqueous solubility of ESL, CBZ and OXC[43]. At physiologic pH of 7.4 at 25 °C, the log P value (n-octanol/water partition coefficient) is 8.8. According to the biopharmaceutic classification system (BCS) which categorizes drugs according to their water solubility and capability to pass across membranes, ESL belongs to BCS class II i.e., a highly permeable-poorly soluble drug[44],[45].

  4. Mechanism of action Top

Voltage-gated sodium channel (VGSC) is the target site of ESL. VGSC is responsible for generation and propagation of the epileptic discharge. VGSC have three states viz. deactivated state, a state of depolarization and inactivated state. In VGSC, ESL interacts with neurotoxin site II [46],[47]. It showed more affinity for inactivated state in comparison to a deactivated state which results in highly selective blockage of the rapid repetitive firing of neurons in in-vitro studies[48],[49],[50]. ESL proved to be efficacious in the amygdala-kindled rat model and various other animal models against pro-convulsant agents such as metrazole, bicuculline, 4-amino-pyridine, latruncullin, and picrotoxin[51],[52].

  5. Pharmacokinetics Top

ESL is known to exhibit linear and dose-proportional (400-1 200 mg/day) pharmacokinetics in both healthy subjects and patients. ESL half life was found to be 13-20 h in patients. One dose a day, give steady-state plasma concentrations after 4-5 d[27],[28],[53].

5.1. Absorption

ESL after oral administration is mainly undetectable with 0.01% systemic exposure. Plasma concentration (Cmax) of ESL is achieved at 14 h of the post-dose peak. Total of 90% of the dose of ESL is recovered in urine that consequently results in high bioavailability (>90%). Tmax and volume of distribution (Vd) of ESL are 1-4 h and 61 L, respectively. ESL shows 20 mL/min, 80-120 mL/min of clearance and glomerular filtration rate, respectively[53],[54].

5.2. Distribution

ESL shows fewer plasma proteins binding (about <40%) which is not concentration dependent. Warfarin, diazepam, digoxin, phenytoin, or tolbutamide does not influence plasma proteins binding of ESL in in-vitro studies and vice versa[27].

5.3. Metabolism

Once ESL is administrated orally, it undergoes major hepatic and minor intestinal metabolism. The hydrolytic metabolism of ESL produces an active metabolite eslicarbazepine (91%). It also results in minor active metabolites R-licarbazepine (5%) and OXC (1%). Initially, ESL is metabolised to eslicarbazepine and then consequently by oxidation a minor chiral inversion takes place to (R)-licarbazepine [Figure 1][55-57]. ESL in in-vitro studies in human liver microsomes had no clinically significant inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1, and CYP3A4[58-60]. Although, it exhibits a modest inhibitory effect on CYP2C19. In human hepatic microsomes, ESL exhibits mild activation of UGT1A1-mediated glucuronidation. ESL in fresh human hepatocytes had no induction of enzymes involved in glucuronidation and sulfation of 7-hydroxy-coumarin[61].
Figure 1: Metabolic pathways of ESL and OXC to eslicarbazepine and (R)-licarbazepine.

Click here to view

5.4. Excretion

The unchanged and glucuronide conjugated forms of ESL metabolites amounting to more than 90% of total metabolites are excreted in urine from the systemic circulation. The metabolites are excreted 2/3 in the unchanged form and 1/3 as a glucuronide conjugate. Total of 10% of the other minor metabolites are also excreted in the urine. The lower renal clearance rate of ESL in comparison to the glomerular filtration rate (20 mL/min < 80-120 mL/min) in healthy subjects is indicative of renal tubular reabsorption[62],[63],[64].

5.5. Specific populations (Geriatrics, gender and race)

The pharmacokinetic of ESL in elderly subjects is found to be unaffected with creatinine clearance of >60 mL/min in comparison to the subjects of age 18-40 years. Therefore, in geriatrics, no ESL dose adjustment is required. Pharmacokinetics was unaffected in healthy subjects’ studies in term of gender. A clinical study involving Caucasian (n=849), Black (n=53), Asian (n=65) and other (n=51) population did not find any relevant effect of race on the pharmacokinetics of ESL.

ESL metabolites are mainly eliminated by renal excretion. A slightly slower elimination rate was observed in renal impairment patients when compared to healthy subjects. The elimination rate in renal impairment patients and healthy subjects were noted to be 10.2 mL/min and 17. 3 mL/min, respectively. However, dose adjustment is required in the patients with creatinine clearance below 50 mL/min[65],[66],[67].

5.6. Hepatic impairment

After multiple oral doses of ESL in healthy subjects, pharmacokinetics was evaluated on the basis of 7-9 points on the Child-Pugh assessment. No relevant effect of ESL clearance was observed in mild or moderate hepatic failure patients hence these patients don’t require any dose adjustment[56],[68],[69].

  6. Safety and tolerability Top

Safety and tolerability of ESL were evaluated by several studies in various diverse regions. Commonly reported adverse events includes hyponatraemia (114), convulsion (48), dizziness (29), fatigue (25), blood sodium decreased (21), vertigo (18) and rash (17)[70],[71],[72],[73],[74]. Rogin et al[75] performed a study of pooled analysis on the adult patients (n=825) with refractory partial onset seizures to evaluate the tolerability of ESL as an adjuvant therapy. They were given OD dose of ESL 800 mg (n=415) or 1 200 mg (n=410) while 426 patients received placebo only. Apart from blurred vision, all treatment showed a dose response relationship. Commonly occurred adverse events were found as:

Dizziness: 19.8% (800 mg), 28.3% (1 200 mg), 9.4 % (placebo); Somnolence: 12.5% (800 mg), 14.9% (1 200 mg), 9.4 % (placebo); Headache: 12.5% (800 mg), 14.9% (1 200 mg), 9.4 % (placebo).

Krauss et al[76] accomplished a pooled analysis to evaluate the effects of starting dose and dose titration scheme in ESL treatment patients. It was observed that ESL 800 mg ‘without-titration’ group and the ESL 800 mg ‘with-titration’ group varies a lot in treatment-emergent adverse events in the second week of treatment. The patients who do not go dose titration showed more adverse events. Similarly, 800 mg initiated dose of ESL showed more adverse events in comparison to 400 mg dose. Authors further reported that 1 200 mg dose exhibits more rashes as compared to 800 mg dose. Whereas, when patient initiated with 800 mg dose the rashes were not found to be high in comparison to 400 mg dose[76].

Costa et al[77] conducted a phase III, multicentre open-label non controlled study. This study involved 72 patients who were treated with one or two AEDs with age ⩾65 years and had at least two partial onset seizures during two month baseline period (treated with 1-2 AEDs). Based on dose-individual response, the dose was maintained (400-1 200 mg) for 26 wk. Dizziness, somnolence, fatigue, convulsion and hyponatraemia were the commonly observed adverse events and were of mild to moderate intensity[77].

Several other studies were conducted to evaluate the safety and tolerability of ESL. Dizziness, nausea, somnolence and hyponatraemia were the commonly noted adverse events. A total of 2.7%-6.6% patient who were given ESL showed adverse events in these studies[78],[79],[80].

  7. Toxicology Top

Some of the important studies conducted to investigate the toxicological profile of ESL are summarized in [Table 1].
Table 1: Toxicology study of ESL.

Click here to view

  8. Drug interaction Top

8.1. Human liver microsomes

ESL does not have any effect on CYP isoforms—CYP1A2, CYP2A6, CYP2B6, CYP2D6 and CYP2E1, CYP3A4, and CYP4A9/11[82]. ESL have minimal or no inhibitory effects on human liver microsomes and on some enzymes like UGT1A1, UGT1A6 and the epoxide hydrolase[83]. CYP2C9-mediated 4-hydroxylation of tolbutamide is moderately affected by ESL. Bialer et al[56] illustrated that ESL in fresh human hepatocyctes does not induce phase Π hepatic enzymes, CYP1A2, and CYP3A4, responsible for glucuronidation and sulfation[56]. Interestingly, ESL was shown to inhibit CYP2C19 at therapeutic concentration[84]. Incubation of 14C ESL with other AEDs (acetazolamide, clobazam, clonazepam, gabapentin, lamotrigine, phenobarbital, primidone and valproic acid) does not inhibit ESL metabolism[85].

8.2. Population pharmacokinetics studies

In ESL phase III clinical studies, epileptic patients were administered concomitantly with other AED such as CBZ (n=526), lamotrigine (n=203), and valproic acid (n=209). The pooled population pharmacokinetic analysis concludes that oral clearance of topiramate CBZ and lamotrigine get enhanced by 15%, 14% and 12% respectively. The clinical significance of this enhancement in oral clearance was not observed, hence the study does not recommend dose adjustment. Also, ESL does not affect the oral clearance of clobazam, gabapentin, levetiracetam, phenobarbital, phenytoin and valproic acid[86].

8.3. Interactions with other AEDs

8.3.1. Phenytoin, phenobarbital, and carbamazepine

A study reported that the co-administration of ESL (1 200 mg/day) and phenytoin (300 mg/day) in healthy patients (n=16) for 27 d caused enhancement in AUC and Cmax by 30%-35% which is probably due to the inhibition of CYP2C19 by ESL. The geometric mean ratio was 117%-146% BIAL. If ESL is concomitantly administered with phenytoin, the dose needs to be decreased. ESL oral clearance is enhanced if the patient is administered phenytoin, phenobarbital, and CBZ. If ESL is concomitantly administered with CBZ, it increases the probability of adverse events as compared to the ESL concomitantly administered with other AEDs[83],[87].

8.3.2. Lamotrigine

Both ESL and lamotrigine are metabolised by glucuronidation pathway. A study carried out in 16 healthy subjects in which ESL and lamotrigine were co-administered for duration of 19 d. The AUC, Cmax for ESL and lamotrigine were noted to be 95%, 96% and 88%, 86%, respectively. The data indicated that there was no substantial pharmacokinetic interaction between ESL and lamotrigine in the healthy subject and therefore their co-administration does not require dose adjustment[88].

8.3.3. Topiramate

Concomitant administration of ESL and Topiramate have no relevant change in ESL plasma exposure but Topiramate plasma exposure decreases by 18%, and the reason for this decline plasma concentration is the enzyme induction[89],[90].

8.3.4. Other AEDs

Apart from above mentioned drugs Clobazam, gabapentine, levetiracetam, topiramate and valproic acid do not exhibit any significant affects on ESL plasma exposure (BIAL-data on file). Therefore no dose adjustment is recommended for any of these AEDs[89].

8.4. Interactions with other drugs

8.4.1. Oral contraceptives

A study involving 20 healthy females reported that ESL lowers and alters the effectiveness of oral contraceptives if ESL and oral contraceptives are used concurrently. Therefore a woman on ESL treatment is recommended to consider other contraception methods[91],[92],[93].

8.4.2. Warfarin

Concomitant use of ESL and warfarin leads to a significant decrease in (S)-warfarin (potent enantiomer) plasma exposure level. However, no significant effects were noted on (R)-warfarin. The (S)-warfarin Cmax and AUC were noted to be 81% and 77% respectively[94],[95],[96].

8.4.3. Simvastatin

Published data recommend adjusting and increasing the dose of simvastatin whenever simvastatin is used concomitantly with ESL. The simvastatin undergoes CYP3A4-mediated oxidative metabolism. Therefore, CYP3A4 induction by ESL is the reason behind this pharmacokinetic interaction which requires elevated simvastatin dose[97].

8.4.4. Metformin

A study by Rocha et al[98] demonstrated that ESL had no clinical significance on metformin pharmacokinetic. The metformin plasma exposure was also found to be unaffected by ESL. A two way cross over, randomized open label study was performed in the healthy patient (n=20). After pre-treatment with ESL (1 200 mg/day), single dose metformin (850 mg) was administrated. The metformin Cmax and AUC were found to be 88% and 95% respectively and hence no significant effects of ESL on metformin was observed[98].

8.4.5. Digoxin

A two-way crossover, randomized on healthy patients (n=12) showed that ESL does not have any clinically significant effect on digoxin pharmacokinetics; therefore no dose adjustment is recommended[99].

  9. Contraindications Top

ESL is contraindicated in some dermatologic reactions such as Stevens-Johnson Syndrome[26],[28] and therefore use of ESL should be discontinued. ESL is also contraindicated in drug reaction with eosinophilia and in symptoms of multiorgan hypersensitivity. The multiorgan hypersensitivity is characterised by fever, rash, lymphadenopathy, eosinophilia and other organ failure. If alternative etiology for symptoms was unable to develop then ESL should be discontinued. Rarer report of anaphylactic reactions and angioedema are also reported[100],[101].

  10. Adverse reactions Top

10.1. Suicidal behaviour and ideation

ESL was found to augment depression of central nervous system (CNS), consequently increasing the risk of suicidal thoughts, behaviour and indication of depression. ESL administration may also cause mood swings in some patients[67],[101],[102].

10.2. Serious dermatologic reactions

ESL may lead to Stevens-Johnson syndrome. It causes serious or sometimes fatal dermatologic reactions. It may also lead to toxic epidermal necrolysis[68],[103].

10.3. Drug reaction with eosinophilia and systemic symptoms/Multiorgan hypersensitivity

ESL administration may cause Drug Reaction with Eosinophilia and Systemic Symptoms. It is known as Multiorgan Hypersensitivity which may be fatal or life-threatening. It is characterised by fever, rash, lymphadenopathy, hepatitis, nephritis, haematological abnormalities, myocarditis, or myositis and viral infection. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately[103],[104].

10.4. Anaphylactic Reactions and Angioedema

ESL administration infrequently causes anaphylactic reactions. Laryngeal edema caused by anaphylaxis and angioedema can be fatal. It is suggested that ESL should be discontinued if a patient is found to have any of these conditions[67],[104].

10.5. Hyponatremia

ESL may cause hyponatremia. In a controlled epilepsy trial more percentage of ESL treated patients experienced lower sodium values in comparison to the placebo-treated patients. The effects arose in first eight weeks of treatment. All effects were found to be dose-related. Hyponatremia due to ESL may lead to serious and life threatening complications which include seizures, nausea, vomiting, dehydration, severe gait instability and injury. Serious cases required hospitalization. Hyponatremia further causes hypochloremia. The dose of ESL should be reduced or discontinued depending on the patient’s severity[69],[105].

10.6. Neurological adverse reactions

10.6.1. Dizziness

Dizziness, ataxia, vertigo, balance disorder, gait disturbance, nystagmus and abnormal coordination were caused by the administration of ESL. A controlled epilepsy trial performed at the doses of 800 mg and 1 200 mg/day showed 26% and 38% of these events respectively when compared to 12% of placebo patients. It was found that events were more often serious in ESL treated patients than in placebo patients (2%, 0%). Increased risks of these events have been found in titration period and in geriatrics patients as compared to maintenance period and younger ones[68],[104],[106].

10.6.2. Somnolence and fatigue

Dose dependent increases in somnolence and fatigue-related adverse reactions like fatigue, asthenia, malaise, hypersomnia, sedation, and lethargy was observed after ESL administration. The controlled epilepsy trials revealed that these events were reported in placebo patients (13%), randomized patients with 800 mg/day (16%) and 1 200 mg/day (28%). The event was found to be serious in 0.3% of patients and caused discontinuation in 3% patients[68],[104],[105].

10.6.3. Cognitive dysfunction

Cognitive dysfunction including memory impairment, disturbance in attention, amnesia, state of confusion, aphasia, speech disorder, slowness of thought, disorientation and psychomotor retardation are increased by ESL therapy a in dose dependent manner. The controlled epilepsy trials revealed the placebo patients (1%), 800 mg/day ESL (4%) and 1200 mg/day ESL patients (7%) showed these events. The drug administration caused seriousness and discontinuation in 0.2% and 1.0% of the patients[69],[102],[103].

10.6.4. Visual changes

Diplopia, blurred vision, and impaired vision are some of the dose dependent events caused by ESL. Total of 16% randomized patient who were administered ESL in controlled epilepsy trials showed these events when compared to 6% of placebo patients. About 0.7% and 4% of ESL treated patient show seriousness and discontinuation respectively. Titration period (compared to the maintenance period) and geriatric patients (compared to younger adults) illustrate high risk of these events[102], [105].

10.7. Withdrawal of AEDs

ESL may enhance the risk of high seizure frequency and status epilepticus with concomitant use of other AEDs. So it is recommended to withdraw the other AEDs to avoid adverse events[69], [106].

10.8. Drug induced liver injury

ESL administration leads to hepatic effects which are more than three times mild to moderate in elevation of the transaminases. It was suggested to have regular baseline evaluations of liver function tests (LFTs). It has been recommended to discontinue ESL in jaundice and other liver injuries[67],[107].

10.9. Abnormal thyroid function tests

ESL administration lowers the serum T3 and T4 (free and total) values in a dose dependent manner[106],[108].

  11. Overdosage Top

ESL overdose leads to symptoms like hyponatremia, dizziness, nausea, vomiting, somnolence, euphoria, oral paraesthesia, ataxia, walking difficulties, and diplopia. Unfortunately, there is no specific antidote for the overdose of ESL. Symptomatic and supportive treatment is recommended for overdose toxicity. The overdose of ESL may be overcome by the removal of the drug by gastric lavage and/or inactivation by administering activated charcoal (adsorbant). Based on patients clinical situation, haemodialysis may be recommended and partial clearance of ESL may be achieved by standard haemodialysis procedures[109],[110],[111].

  12. Conclusion Top

ESL, a third generation, single enantiomeric dibenzazepine family member is limited to partial-onset and generalized tonic-clonic seizures. In the diverse model of species, ESL undergoes extensive first pass metabolism to its major active metabolite eslicarbazepine. ESL is found to be effective as adjunctive therapy in adult patients with refractory partial-onset seizures. The most promising dose of ESL is between 800 and 1 200 mg. ESL monotherapy patients experienced a fall in seizure frequency when compared with baseline. When ESL is used as a monotherapy the relatively elevated completion rate and the adverse events profile at doses of 1 200 and 1 600 mg once daily demonstrate that ESL is efficacious and well tolerated. ESL not only confirmed a therapeutic effect as the addon treatment for partial-onset seizures in adults but also sustained efficacy during long term study. ESL has minimal adverse effects like dizziness, somnolence, headache, nausea and vomiting. The drug has a distinct mechanism of action, posology and pharmacokinetic profile as compared to other existing AEDs. It exhibits linear pharmacokinetics in both genders with moderate liver impairment. It requires dose adjustment in renal impairment patients because it is eliminated primarily by renal excretion. ESL is the most acceptable AED as it has least drug-drug interactions at pharmacodnamic and pharmacokinetic level. Phenobarbital, phenytoin, and carbamazepine may induce ESL clearance and oral contraceptive decreases plasma exposure in a dose-dependent manner thus it is recommended to be used with precautions in female.

Conflict of interest statement

We declare that we have no conflict of interest.

  References Top

Fiest KM, Sauro KM, Wiebe S, Patten SB, Kwon CS, Dykeman J, et al. Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies. Neurology 2017; 88: 296-303.  Back to cited text no. 1
Moshe SL, Perucca E, Ryvlin P, Tomson T. Epilepsy: New advances. Lancet 2015; 385: 884-898.  Back to cited text no. 2
Robertson J, Baines S, Emerson E, Hatton C. Service responses to people with intellectual disabilities and epilepsy: A systematic review. J Appl Res Intellect Disabil 2017; 30: 1-32.  Back to cited text no. 3
Banerjee PN, Filippi D, Allen Hauser W. The descriptive epidemiology of epilepsy - A review. Epilepsy Res 2009; 85: 31-45.  Back to cited text no. 4
Chong DJ, Lerman AM. Practice update: Review of anticonvulsant therapy. Curr Neurol Neurosci Rep 2016; 16: 39.  Back to cited text no. 5
Tabaeizadeh M. Review of antiepileptic drugs. JAMA Neurol 2016; 73: 896.  Back to cited text no. 6
Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, Van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology. Epilepsia 2010; 51(4): 676-685.  Back to cited text no. 7
Modi AC, Wagner J, Smith AW, Kellermann TS, Michaelis R. Implementation of psychological clinical trials in epilepsy: Review and guide. Epilepsy Behav 2017; 74: 104-113.  Back to cited text no. 8
Faught E. Adherence to antiepilepsy drug therapy. Epilepsy Behav 2012; 25: 297-302.  Back to cited text no. 9
Bial E. Announce partnership agreement for the European commercialisation of the novel once daily antiepileptic zebinix; 2009 [Online] Available from: http://www.pmewswire.co.uk/newsreleases/...153037325.html). [Accessed on 1st June, 2017].  Back to cited text no. 10
Summary of Product Characteristics for Zebinix. [Online] Available from: (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000988/WC500047225.pdf). [Accessed on 22 June, 2017].  Back to cited text no. 11
Exalief (eslicarbazepine acetate): Expiry of the marketing authorisation in the European Union. [Online] Available from: (http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2012/08/WC500130787.pdf). [Accessed on 2 Jan 2017].  Back to cited text no. 12
FDA approves Aptiom to treat seizures in adults; 2013 [Online] Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm374358.htm. [Accessed on 15 March, 2017]  Back to cited text no. 13
Zaccara G, Giovannelli F, Maratea D, Fadda V, Verrotti A. Neurological adverse events of new generation sodium blocker antiepileptic drugs. Meta-analysis of randomized, double-blinded studies with eslicarbazepine acetate, lacosamide and oxcarbazepine. Seizure 2013; 22(7): 528-536.  Back to cited text no. 14
Serralheiro A, Alves G, Fortuna A, Rocha M, Falcão A. First HPLC-UV method for rapid and simultaneous quantification of phenobarbital, primidone, phenytoin, carbamazepine, carbamazepine-10, 11-epoxide, 10, 11-trans-dihydroxy-10, 11-dihydrocarbamazepine, lamotrigine, oxcarbazepine and licarbazepine in human plasma. J Chromatogr B 2013; 15: 1-9.  Back to cited text no. 15
EPAR EMEA Zebinix. Document H-988-en6 eslicarbazepine acetate, scientific discussion in the public assessment report for Zebinix (eslicarbazepine acetate INN) [Online] Available from: http://www.emea.europa.eu/humandocs/Humans/EPAR/zebinix/zebinix.htm [Accessed on 10 april, 2017].  Back to cited text no. 16
Mula M. Recent and future antiepileptic drugs and their impact on cognition: What can we expect? Expert Rev Neur 2012; 12(6): 667-671.  Back to cited text no. 17
Chaves J, Breia P, Pimentel J, Pelejão R, Carvalho M, Mateus P, et al. Eslicarbazepine acetate as adjunctive therapy in clinical practice: ESLADOBA study. Acta Neurol Scand 2017; DOI: 10.1111/ane.12734.  Back to cited text no. 18
Luszczki JJ. Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions. Pharmacolo Rep 2009; 61(2): 197-216.  Back to cited text no. 19
Gabbai AA, Ben-Menachem E, Maia J, Almeida L. Long-term treatment of partial epilepsy with eslicarbazepine acetate. Epilepsia 2008; 49: 432-433.  Back to cited text no. 20
Parada CA, Crowley S, Lynch B, Webb DW. A retrospective audit of eslicarbazepine acetate (Zebinix) use an Irish paediatric population. Eur J Paed Neur 2017; 21: 33-40.  Back to cited text no. 21
Loscher W. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure 2011; 20(5): 359-368.  Back to cited text no. 22
Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T. Progress report on new antiepileptic drugs: A summary of the EigthEilat Conference (EILAT VIII). Epilepsy Res 2007; 73(1): 1-52.  Back to cited text no. 23
Peltola J, Holtkamp M, Rocamora R, Ryvlin P, Sieradzan K, Villanueva V. Practical guidance and considerations for transitioning patients from oxcarbazepine or carbamazepine to eslicarbazepine acetate-Expert opinion. Epilepsy Behav 2015; 50: 46-49.  Back to cited text no. 24
Zhang C, Zuo Z, Kwan P, Baum L. In vitro transport profile of carbamazepine, oxcarbazepine, eslicarbazepine acetate, and their active metabolites by human P-glycoprotein. Epilepsia 2011; 52(10): 1894-1904.  Back to cited text no. 25
Brodie MJ. Sodium channel blockers in the treatment of epilepsy. CNS Drugs 2017; 18: 1-8.  Back to cited text no. 26
Serrano-Castro PJ, Payán-Ortiz M, Cimadevilla JM, Quiroga-Subirana P, Fernández-Pérez J. Eslicarbazepine acetate in clinical practice. Efficacy and safety results. Revista de Neurologia 2013; 56(6): 309-314.  Back to cited text no. 27
Smetana KS, Cook AM, Bastin ML, Oyler DR. Antiepileptic dosing for critically ill adult patients receiving renal replacement therapy. J Criti Care 2016; 36: 116-124.  Back to cited text no. 28
Brady K, Hebeisen S, Konrad D. The effects of Eslicarbazepine, R-Licarbazepine, Oxcarbazepine and Carbamazepine on ion transmission through Cav3. 2 channels. Epilepsia 2011; 52: 260.  Back to cited text no. 29
Nunes T, Rocha J, Falcao A, Almeida L, Soares-Da-Silva P. Steady-state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteers. Epilepsia 2013; 54: 108-116.  Back to cited text no. 30
Hebeisen S, Pires N, Loureiro AI, Bonifácio MJ, Palma N, Whyment A, et al. Eslicarbazepine and the enhancement of slow inactivation of voltage-gated sodium channels: A comparison with carbamazepine, oxcarbazepine and lacosamide. Neur Pharmacol 2015, 89: 122-135.  Back to cited text no. 31
Aptiom [package insert]. Marlborough. MA: Sunovion Pharmaceuticals Inc; 2013.  Back to cited text no. 32
Sunkaraneni S, Bihorel S, Hopkins S, Fiedler-Kelly J, Ludwig E, Galluppi G, et al. Modeling and simulation strategy to support eslicarbazepine acetate (ESL) paediatric dose selection in the treatment of partial onset seizures based on matching adult exposures. Neurology 2017; 88: P3,246.  Back to cited text no. 33
Eslicarbazepine. Clinical pharmacology [Internet Database]. Gold Standard, Inc., 2009. [Online] Available from: http://www.clinicalpharmacology.com [Accessed on 12 June; 2017].  Back to cited text no. 34
Galiana GL, Gauthier AC, Mattson RH. Eslicarbazepine acetate: A new improvement on a classic drug family for the treatment of partial-onset seizures. Drugs R & D 2017; 1: 1.  Back to cited text no. 35
Zaccara G, Giovannelli F, Cincotta M, Carelli A, Verrotti A. clinical utility of eslicarbazepine: Current evidence. Drug Design Dev Ther 2015; 9: 781.  Back to cited text no. 36
Svendsen T, Brodtkorb E, Reimers A, Molden E, Sætre E, Johannessen SI, et al. Pharmacokinetic variability, efficacy and tolerability of eslicarbazepine acetate-A national approach to the evaluation of therapeutic drug monitoring data and clinical outcome. Epilep Res 2017; 129: 125-131.  Back to cited text no. 37
Almeida L, Soares-da-silva P. Safety, tolerability and pharmacokinetic profile of BIA 2-093, a novel putative antiepileptic agent, during first administration to human. J Clin Pharmacol 2004; 44: 906-918.  Back to cited text no. 38
Keating GM. Eslicarbazepine acetate: A review of its use as adjunctive therapy in refractory partial-onset seizures. CNS Drugs 2014; 28(7): 583-600.  Back to cited text no. 39
Forities C, Numes T, Falcao A. Eslicarbazepine acetate BIA 2-09: relative bioavailability and bioeqyuivalence of 50 mg/mL oral suspension and 200 mg and 800 mg tablet formulation. Drugs R&D 2005; 6: 253-260.  Back to cited text no. 40
Maia J, Almeida L, Falcao A. Effects of renal impairment on the pharmacokinetics of eslicarbazepine acetate. Int J Clin Pharmacol Ther 2008; 46:119-130.  Back to cited text no. 41
Faigle JW, Menge GP. Pharmacokinetics and metabolic features of oxcarbazepine and their clinical significance: Comparison with carbamazepine. Int J Clin Psychopharmacol 1990; 5: 73-82.  Back to cited text no. 42
Flesch G, Czendlik C, Renard D, Lloyd P. Pharmacokinetics of the monohydroxy derivative of oxcarbazepine and its two enantiomers after a single intravenous dose given as racemate compared with a single oral dose of oxcarbazepine. Dru^g Metab Dipso 2011; 39: 1103-1110.  Back to cited text no. 43
Wu CY, Benet LZ. Predicting drug disposition via application of BCS: Transport/absorption elimination interplay and development of biopharmaceutics drug disposition classification system. Pharm Res 2005; 22: 11-23.  Back to cited text no. 44
Rowland M, Tozer T. Clinical pharmacokinetics and pharmacodynamics. 4th ed. Philadelphia: Walter Kluwer; 2010, p. 203-204.  Back to cited text no. 45
Dulsat C, Mealy N, Castaner R, Bolos J. Eslicarbazepine acetate. Drugs Future 2009; 34: 263-286.  Back to cited text no. 46
mbrosio AF, Silva AP, Malva JO, Soares-da-Silva P, Carvalho AP, Carvalho CM. Inhibition of glutamate release by BIA 2-093 and BIA 2-024, two novel derivatives of carbamazepine, due to blockade of sodium but not calcium channels. Biochem Pharmacol 2001; 61(10): 1271-1275.  Back to cited text no. 47
Patsalos PN, Berry DJ. Pharmacotherapy of the third-generation AEDs: Lacosamide, retigabine and eslicarbazepine acetate. Expert Opin Pharmacother 2012; 13(5): 699-715.  Back to cited text no. 48
Sierra-Paredes G, Oreiro-Garcia MT, Vazquez-Illanes MD, Sierra-Marcuno G. Effect of eslicarbazepine acetate (BIA 2-093) on latrunculin A-induced seizures and extracellular amino acid concentrations in the rat hippocampus. Epilepsy Res 2007; 77(1): 36-43.  Back to cited text no. 49
Rogawski MA, Tofighy A, White HS, Matagne A, Wolff C. Current understanding of the mechanism of action of the antiepileptic drug lacosamide. Epilepsy Res 2015; 110: 189-205.  Back to cited text no. 50
Araujo IM, Ambrosio AF, Leal EC. Neurotoxicity induced by antiepileptic drugs in cultured hippocampal neurons: A comparative study between carbamazepine, oxcarbazepine, and two new putative antiepileptic drugs, BIA 2-024 and BIA 2-093. Epilepsia 2004; 45 (12): 1498-505.  Back to cited text no. 51
Almeida L, Potgieter JH, Maia J, Potgieter MA, Mota F, Soares-da-Silva P. Pharmacokinetics of eslicarbazepine acetate in patients with moderate hepatic impairment. Eur J Clin Pharmacol 2008; 64(3): 267-273.  Back to cited text no. 52
Shirley M, Dhillon S. Eslicarbazepine acetate monotherapy: A review in partial-onset seizures. Drugs 2016; 76(6): 707-717.  Back to cited text no. 53
Velez F, Grinnell T, Siddiqui MK, Blum D. Assessment of eslicarbazepine acetate monotherapy vs. other anti-epileptic drugs for refractory partial-onset seizures: Results of a network meta-analysis using historical-control trials. Neurology 2016; 86: 2-23.  Back to cited text no. 54
Zelano J, Ben-Menachem E. Eslicarbazepine acetate for the treatment of partial epilepsy. Expert Opin Pharmacother 2016; 17(8): 1165-1169.  Back to cited text no. 55
Bialer M. Oxcarbazepine: Chemistry, biotransformation and pharmacokinetics. In: Levy RH, Mattson RH, Meldrum BS, Perucca E. (eds) Antiepileptic drugs. 5th ed. New York: Lippincott Williams & Wilkins Publishers; 2002, p. 459-465.  Back to cited text no. 56
Flesch G. Overview of the clinical pharmacokinetics of oxcarbazepine. Clin Drug Investig 2004; 24: 185-203.  Back to cited text no. 57
Soares-da-Silva P, Pires N, Bonifácio MJ, Loureiro AI, Palma N, Wright LC. Eslicarbazepine acetate for the treatment of focal epilepsy: An update on its proposed mechanisms of action. Pharmacol Res Perspect 2015; 2: 1-3.  Back to cited text no. 58
Landmark CJ, Svendsen T, Dinarevic J, Kufaas RF, Reimers A, Brodtkorb E, et al. The impact of pharmacokinetic interactions with eslicarbazepine acetate versus oxcarbazepine and carbamazepine in clinical practice. Ther Drug Monit 2016; 38(4): 499-505.  Back to cited text no. 59
Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress report on new antiepileptic drugs: A summary of the Ninth Eilat Conference (EILAT IX). Epilepsy Res 2009; 83: 1-43.  Back to cited text no. 60
Perucca E, Elger C, Halasz P, Falcao A, Almeida L, Soares-da-Silva P. Pharmacokinetics of eslicarbazepine acetate at steady-state in adults with partial-onset seizures. Epilepsy Res 2011; 96: 132-139.  Back to cited text no. 61
Almeida L, Falcão A, Maia J, Mazur D, Gellert M, Soares-da-Silva P. Single-dose and steady-state pharmacokinetics of eslicarbazepine acetate (BIA 2-093) in healthy elderly and young subjects. J Clin Pharmacol 2005; 45: 1062-1066.  Back to cited text no. 62
Yu J, Ritchie TK, Mulgaonkar A, Ragueneau-Majlessi I. Drug disposition and drug-drug interaction data in 2013 FDA new drug applications: A systematic review. Drug Metab Disp 2014; 42(12);1991-2001.  Back to cited text no. 63
Tambucci R, Basti C, Maresca M, Coppola G, Verrotti A. Update on the role of eslicarbazepine acetate in the treatment of partial-onset epilepsy. Neuropsych Dis Treat 2016; 12: 1251.  Back to cited text no. 64
Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T. Progress report on new antiepileptic drugs: a summary of the Seventh Eilat Conference (EILAT VII). Epilepsy Res 2004; 61: 1-48.  Back to cited text no. 65
Finsterer J, Gelpi E. Mitochondrial disorder aggravated by propranolol. South Med J 2006; 99(7): 768-772.  Back to cited text no. 66
European Medicines Agency Find Medicine Zebinix [Online] Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000988/human_med_001172.jsp&mid=WC0b01ac058001d12[Accessed on 5 March; 2017].  Back to cited text no. 67
FDA Professional Drug Information about Aptiom. EMEA/CHMP Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function [Online] Available at: https://www.drugs.com/pro/aptiom.html. [Accessed on 1 October 2005].  Back to cited text no. 68
Vaz-da-Silva M, Nunes T, Soares E, Rocha JF, Tavares S, Falcão A, et al. Eslicarbazepine acetate pharmacokinetics after single and repeated doses in healthy subjects. Epilepsia 2005; 46: 191.  Back to cited text no. 69
Elger C, Bialer M, Cramer JA, Maia J, Almeida L, Soares-da-Silva P. Eslicarbazepine acetate: A double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures. Epilepsia 2007; 48(3): 497-504.  Back to cited text no. 70
Hainzl D, Parada A, Soares-da-Silva P. Metabolism of two new antiepileptic drugs and their principal metabolites S and R-10, 11-dihydro-10-hydroxyl carbamazepine. Epilepsy Res 2001; 44(2-3): 197-206.  Back to cited text no. 71
Derambure P, Mcmurray R, Sousa R, Holtkamp M. Eslicarbazepine acetate as add-on to antiepileptic monotherapy in adults with partial-onset seizures (EPOS study): Analysis by baseline antiepileptic drug. Epilepsia 2015; 56: 54.  Back to cited text no. 72
Alves G, Fortuna A, Sousa J, Direito R, Almeida A, Rocha M, et al. Enantioselective assay for therapeutic drug monitoring of eslicarbazepine acetate: No interference with carbamazepine and its metabolites. Ther Drug Monit 2010; 32(4): 512-516.  Back to cited text no. 73
Toledano R, Jovel CE, Jiménez-Huete A, Bayarri PG, Campos D, Gomariz EL, et al. Efficacy and safety of eslicarbazepine acetate monotherapy for partial-onset seizures: Experience from a multicenter, observational study. Epilepsy Behav 2017; 73: 173-179.  Back to cited text no. 74
Rogin J, Abou-Khalil B, Blum D, Sousa R, Grinnell T. Eslicarbazepine acetate as adjunctive treatment for refractory partial-onset seizures: Pooled analysis of safety data from three phases Π controlled trials [abstract 2.126]. Epilepsy Currents 2014; 14: 209.  Back to cited text no. 75
Krauss G, Biton V, Harvey J, Blum D, Sousa R, Grinnell T. Adverse event profile of eslicarbazepine acetate during dose titration in phase Π controlled studies of patients with refractory partial on set seizures [abstract 3.208]. Epilepsy Currents 2014; 14: 393-394.  Back to cited text no. 76
Costa R, Oliveira C, Lopes N, Gama H, Sousa R, Nunes T. Safety and efficacy of eslicarbazepine acetate treatment in elderly patients [abstract P340]. Epilepsia 2014; 55: 112.  Back to cited text no. 77
Massot A, Vivanco R, Principe A, Roquer J, Rocamora R. Post-authorisation study of eslicarbazepine as treatment for drug-resistant epilepsy: Preliminary results. Neurologia 2014; 29: 94-101.  Back to cited text no. 78
Serrano-Castro P, Payan-Ortiz M, Cimadevilla J, Quiroga-Subirana P, Fernandez-Perez J. Eslicarbazepine acetate in clinical practice. EfEicacy and safety results. Rev Neurologia 2011; 56: 309-314.  Back to cited text no. 79
Villanueva V, Serratosa J, Guillamon E, Garces M, Giraldez B, Toledo M. Long-term safety and efficacy of eslicarbazepine acetate in patients with focal seizures: results of the 1-year eslibase retrospective study. Epilepsy Res 2014; 108: 1243-1252.  Back to cited text no. 80
Correia FD, Freitas J, Magalhães R, Lopes J, Ramalheira J, Lopes-Lima J, et al. Two-year follow-up with eslicarbazepine acetate: Aconsecutive, retrospective, observational study. Epilepsy Res 2014; 108(8): 1399-1405.  Back to cited text no. 81
American academy of pediatrics committee on drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3): 776-789.  Back to cited text no. 82
Almeida L, Soares-da-Silva P. Eslicarbazepine acetate BIA 2-093. Neurotherapeutics 2007; 4: 88-96.  Back to cited text no. 83
Numes T, Maia J, Almeida L. Pharmacokinetics interaction between eslicarbazepine acetate and lamotrigine in healthy subjects. In: Procedings of the 61st annual meting of the American Epilepsy Society, November 30 - December 04, 2007. Philadelphia, Pennsylvania. Phiadelphi: American Epilepsy Society; 2007.  Back to cited text no. 84
Almeida L, Vaz-da-Silva M, Falcao A. Effect of eslicarbazepine acetate (BIA 2-093) on the steady state pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. In: Procedings of the 7th European congress on Epileptology. Prague, Czech Republic, September 11 to 15, 2016. Helsinki: Commission on European Affairs (CEA) of the International League Against Epilepsy (ILAE); 2006.  Back to cited text no. 85
Maia J, Vaz-da-Siva M, Falcao A. Effects of eslicarbazepine acetate (BIA 2-093) on the steady state pharmacokinetics of digoxin in healthy subjects. Epilepsia 2005; 46: 283.  Back to cited text no. 86
Constantino T, Gidal B, Mintzer S, Grinnell T, Blum D, Cheng H. Markers of bone turnover and lipid metabolism during eslicarbazepine acetate (ESL) monotherapy in patients taking or not taking enzyme-inducing antiepileptic drugs (EIAEDs) at baseline (BL). Neurology 2016; 86: 2-30.  Back to cited text no. 87
Lakehal F, Wurden CJ, Kalhorn TF, Levy RH. Carbamazepine and oxcarbazepine decrease phenytoin metabolism through inhibition of CYP2C19. Epilepsy Res 2002; 52: 79-82.  Back to cited text no. 88
Almeida L, Nunes T, Sicard E, Rocha JF, Falc o A, Brunet JS, et al. Pharmacokinetic interaction study between eslicarbazepine acetate and lamotrigine in healthy subjects. Acta Neurol Scand 2010; 121(4):257-264.  Back to cited text no. 89
Nunes T, Sicard E, Almeida L, Falc o A, Rocha JF, Brunet JS, et al. Pharmacokinetic interaction study between eslicarbazepine acetate and topiramate in healthy subjects. Curr Med Res Opin 2010; 6: 1355-1362.  Back to cited text no. 90
European Medicines Agency. CHMP Assessment Report for Exalief: International Nonproprietary Name: ESL acetate. London, 19 February 2009 [Online]. Available from: http://www.emea.europa.eu/humandocs/PDFs/EPAR/exalief/H-987-en6.pdf. [Accessed on 18 October 2016].  Back to cited text no. 91
Fattore C, Cipolla G, Gatti G, Limido GL, Strum Y, Bernasconi C, et al. Induction of ethinylestradiol and levonorgestrel metabolism by oxcarbazepine in healthy women. Epilepsia 1999; 40: 783-787.  Back to cited text no. 92
McCormack PL, Robinson DM. Eslicarbazepine acetate. CNS Drugs 2009; 23(1): 71-79.  Back to cited text no. 93
Almeida L, Falc o A, Maia J, Vaz-da-Silva M, Soares E, Soares-da-Silva P. Steady-state pharmacokinetics of once-daily and twice-daily regimens of eslicarbazepine acetate (BIA 2-093) in healthy subjects. AES Proc Epilepsia 2006; 154.  Back to cited text no. 94
Almeida L, Vaz-da-Silva M, Falco A, Maia J, Soares E, Soares-da-Silva P. Effect of eslicarbazepine acetate (BIA 2-093) on the steady state pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. In: Proceedings of the 7th European Congress on Epileptology, Prague, Czech Republic, September 11 to 15, 2016. Helsinki: Commission on European Affairs (CEA) of the International League Against Epilepsy (ILAE); 2006.  Back to cited text no. 95
Vaz-da-Silva M, Almeida L, Falco A, Soares E, Maia J, Nune T, et al. Effect of eslicarbazepine acetate on steady-state pharmacokinetics and pharmacodynamics of warfarin in healthy subjects during a three stage, open-label, multiple-dose, single-period study. Clin Ther 2010; 32: 179-192.  Back to cited text no. 96
Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet 1993; 24: 195-202.  Back to cited text no. 97
Rocha JF, Vaz-da-Silva M, Almeida L. Effect of eslicarbazepine acetate on the pharmacokinetics of metformin in healthy subjects. Int J Clin Pharmacol Ther 2009; 47(4): 255-261.  Back to cited text no. 98
Vaz da Silva, Costa R, Saoares E. Effect of eslicarbazepine acetate on the pharmacokinetics of digoxin in healthy subjects. Fundam Clin Pharmacol 2009; 23(4): 509-514.  Back to cited text no. 99
Kay L, Willems LM, Zöllner JP, Reif PS, Klein KM, Rosenow F, et al. Eslicarbazepine acetate as a therapeutic option in a patient with carbamazepine-induced rash and HLA-A31: 01. Seizure 2017; 47: 81-82.  Back to cited text no. 100
Keogh S, McDonald P, Lawthom C, Brodie M, Mclean B, Damodaran D. Safety and efficacy of eslicarbazepine acetate (Zebinix) in everyday clinical practice using a retrospective multicentre audit. J Neurol Neurosurg Psych 2014; 85: e4.  Back to cited text no. 101
Bonifacio M, Sheridan R, Parada A, Cunha R, Patmore L, Soares-Da-Silva P. Interaction of the novel anticonvulsant, BIA 2-093, with voltage-gated sodium channels: Comparison with carbamazepine. Epilepsia 2001; 42: 600-608.  Back to cited text no. 102
Lima R, Vasconcelos T, Cerdeira R, Lefebvre M, Sicard E. Bioequivalence of final tablet formulation and research tablet formulation of eslicarbazepine acetate in healthy volunteers. J Bioequiv Availab 2009; 1(3): 93-98.  Back to cited text no. 103
Ambrosio AF, Silva AP, Araujo I, Malva JO, Soares-da-Silva P, Carvalho AP, et al. Neurotoxic/neuroprotective profile of carbamazepine, oxcarbazepine and two new putative antiepileptic drugs, BIA 2-093 and BIA 2-024. Eur J Pharmacol 2000; 406(2): 191-201.  Back to cited text no. 104
Halasz P, Elger C, Ben-Menachem E, Alain-Gabbai A, Lopes-Lima J, Gil-Nagel A. Efficacy and safety of eslicarbazepine acetate as addon treatment to carbamazepine in patients with partial-onset seizure. Epilepsia 2009; 50: 65-66.  Back to cited text no. 105
Marson AG, Al-Kharusi AM, Alwaidh M. The SANAD study of effectiveness of CBZ, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: An unblinded randomised controlled trial. Lancet 2007; 369: 1000-1015.  Back to cited text no. 106
Ortenzi A, Paggi A, Foschi N, Sabbatini D, Pistoli E. Oxcarbazepine and adverse events: Impact of age, dosage, metabolite serum concentrations and concomitant antiepileptic therapy. Funct Neurol 2008; 23:97-100.  Back to cited text no. 107
Kharidia J, Maier G, Versavel M, Blum D, Maia J, Soares-da-Silva P. CSF and plasma pharmacokinetics of eslicarbazepine acetate and oxcarbazepine in healthy subjects. AES Annual Meeting, San Antonio, 2010.  Back to cited text no. 108
Ben-Menachem E. Eslicarbazepine acetate: A well-kept secret? Epilepsy Curr 2010; 10(1): 7-8.  Back to cited text no. 109
Gil-Nagel A, Lopes-Lima J, Almeida L, Maia J, Soares-da-Silva P. Efficacy and safety of 800 and 1 200 mg eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures. Acta Neurol Scand 2009; 120: 281-287.  Back to cited text no. 110
Shah K, Rana D, Patel V. Newer antiepileptic drugs. NHL J Med Sci 2015; 4: 1.  Back to cited text no. 111


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