ESLICARBAZEPINE ACETATE- eslicarbazepine acetate_tablet

Eslicarbazepine acetate are extensively converted to eslicarbazepine, which is considered to be responsible for therapeutic effects in humans. The precise mechanism(s) by which eslicarbazepine exerts anticonvulsant activity is unknown but is thought to involve inhibition of voltage-gated sodium channels. The effect of eslicarbazepine acetate on cardiac repolarization was evaluated in a randomized, double-blind, placebo-and active-controlled 4-period crossover trial in healthy adult men and women. Subjects received eslicarbazepine acetate 1,200 mg once daily × 5 days, eslicarbazepine acetate 2,400 mg once daily × 5 days, an active-control, moxifloxacin 400 mg × 1 dose on Day 5, and placebo once daily × 5 days. At both doses of eslicarbazepine acetate, no significant effect on the QTc interval was detected. The pharmacokinetics of eslicarbazepine is linear and dose-proportional in the dose range of 400 mg to 1,600 mg once daily, both in healthy adult subjects and patients. The apparent half-life of eslicarbazepine in plasma was 13 to 20 hours in adult epilepsy patients. Steady-state plasma concentrations are attained after 4 to 5 days of once daily dosing. Absorption, Distribution, Metabolism, and Excretion Absorption Eslicarbazepine acetate are mostly undetectable (0. 01% of the systemic exposure) after oral administration. Eslicarbazepine, the major metabolite, is primarily responsible for the pharmacological effect of eslicarbazepine acetate. Peak plasma concentrations (Cmax) of eslicarbazepine are attained at 1 to 4 hours post-dose. Eslicarbazepine is highly bioavailable, because the amount of eslicarbazepine and glucuronide metabolites recovered in urine corresponded to more than 90% of an eslicarbazepine acetate dose. Food has no effect on the pharmacokinetics of eslicarbazepine after oral administration of eslicarbazepine acetate. Distribution The binding of eslicarbazepine to plasma proteins is relatively low (< 40%) and independent of concentration. In vitro Metabolism Eslicarbazepine acetate are rapidly and extensively metabolized to its major active metabolite eslicarbazepine by hydrolytic first-pass metabolism. Eslicarbazepine corresponds to 91% of systemic exposure. The systemic exposure to minor active metabolites of (R)-licarbazepine is 5% and oxcarbazepine is 1%. The inactive glucuronides of these active metabolites correspond to approximately 3% of systemic exposure. In in vitro No apparent autoinduction of metabolism has been observed with eslicarbazepine acetate in humans. Excretion Eslicarbazepine acetate metabolites are eliminated from the systemic circulation primarily by renal excretion, in the unchanged and glucuronide conjugate forms. In total, eslicarbazepine and its glucuronide account for more than 90% of total metabolites excreted in urine, approximately two thirds in the unchanged form and one third as glucuronide conjugate. Other minor metabolites account for the remaining 10% excreted in the urine. In healthy subjects with normal renal function, the renal clearance of eslicarbazepine (approximately 20 mL/min) is substantially lower than glomerular filtration rate (80 to 120 mL/min), suggesting that renal tubular reabsorption occurs. The apparent plasma half-life of eslicarbazepine was 13 to 20 hours in epilepsy patients [see Dosage and Administration (2. 4) and Use in Specific Populations (8. Specific Populations Geriatric Patients (>= 65 Years of Age) The pharmacokinetic profile of eslicarbazepine was unaffected in elderly subjects with creatinine clearance > 60 mL/min compared to healthy subjects (18 to 40 years) after single and repeated doses of 600 mg eslicarbazepine acetate during 8 days of dosing. No dose adjustment is necessary in adults based on age, if CrCl is >= 50 mL/min. Pediatric Patients (4 to 17 Years of Age) A pharmacokinetic study of eslicarbazepine acetate was performed in 29 pediatric patients with partial-onset seizures. Limited pharmacokinetic sampling was also performed during controlled pediatric adjunctive therapy partial-onset seizure studies. As in adult patients, eslicarbazepine acetate is rapidly and extensively metabolized to its major active metabolite eslicarbazepine. The pharmacokinetics of eslicarbazepine is linear and dose-proportional in the dose range of 5 to 30 mg/kg/day. Peak plasma concentrations (C max A population pharmacokinetic analysis showed that body weight significantly correlates with the clearance of eslicarbazepine in pediatric patients; clearance increased with an increase in body weight. A weight-based dosing regimen is necessary to achieve eslicarbazepine exposures in pediatric patients aged 4 to 17 years similar to those observed in adults treated at effectives doses of eslicarbazepine acetate [see Dosage and Administration (2. 2)] The pharmacokinetics of eslicarbazepine in pediatric patients are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures. Gender Studies in healthy subjects and patients showed that pharmacokinetics of eslicarbazepine was not affected by gender. Race No clinically significant effect of race (Caucasian N=849, Black N=53, Asian N=65, and Other N=51) on the pharmacokinetics of eslicarbazepine was noted in a population pharmacokinetic analysis of pooled data from the clinical studies. Renal Impairment Eslicarbazepine acetate metabolites are eliminated from the systemic circulation primarily by renal excretion. The extent of systemic exposure of eslicarbazepine following an 800 mg single dose was increased by 62% in patients with mild renal impairment (CrCl 50 to 80 mL/min), by 2-fold in patients with moderate renal impairment (CrCl 30 to 49 mL/min) and by 2. 5-fold in patients with severe renal impairment (CrCl 80 mL/min). Dosage adjustment is recommended in patients with creatinine clearance below 50 mL/min [see Dosage and Administration (2. In patients with end stage renal disease, repeated hemodialysis removed eslicarbazepine acetate metabolites from systemic circulation. Hepatic Impairment The pharmacokinetics and metabolism of eslicarbazepine acetate was evaluated in healthy subjects and patients with moderate liver impairment (7 to 9 points on the Child-Pugh assessment) after multiple oral doses (see Figure 1). Moderate hepatic impairment did not affect the pharmacokinetics of eslicarbazepine acetate. No dose adjustment is recommended in patients with mild to moderate liver impairment. The pharmacokinetics of eslicarbazepine acetate has not been studied in patients with severe hepatic impairment. Figure 1: Impact of Intrinsic Factors on AUC of Eslicarbazepine Drug Interaction Studies Potential for Other AEDs to Affect Eslicarbazepine The potential impact of other AEDs on the systemic exposure (area under the curve, AUC) of eslicarbazepine, the active metabolite of eslicarbazepine acetate, is shown in Figure 2: Figure 2: Potential Impact of Other AEDs on AUC of Eslicarbazepine Potential for Eslicarbazepine Acetate to Affect Other Drugs The potential impact of eslicarbazepine acetate on the systemic exposure (AUC) of other drugs (including AEDs) is shown in Figures 3a and 3b: Figure 3a: Potential Impact of Eslicarbazepine Acetate on the AUC of AEDs Figure 3b: Potential Impact of Eslicarbazepine Acetate on the AUC of Non-AEDs image description image description image description image description.

Eslicarbazepine acetate tablets are indicated for the treatment of partial-onset seizures in patients 4 years of age and older.

Adult Patients: The recommended initial dosage of eslicarbazepine acetate tablets is 400 mg once daily. For some patients, treatment may be initiated at 800 mg once daily if the need for seizure reduction outweighs an increased risk of adverse reactions. Increase the dose in weekly increments of 400 mg to 600 mg once daily, based on clinical response and tolerability, to a recommended maintenance dosage of 800 mg to 1,600 mg once daily. 2 Pediatric Patients: The recommended dosage of eslicarbazepine acetate tablets is based on body weight and is administered orally once daily. Increase the dose in weekly intervals based on clinical response and tolerability, to the recommended maintenance dosage. 2 Patients with Moderate or Severe Renal Impairment: Reduce dosage by 50%. 4 Instruct patients to administer eslicarbazepine acetate tablets either as whole or as crushed tablets. Instruct patients to take eslicarbazepine acetate tablets either with or without food. The eslicarbazepine acetate tablets dosing regimen depends on age, weight, and renal function. Monotherapy and Adjunctive Therapy Adult Patients The recommended initial dosage of eslicarbazepine acetate tablets is 400 mg administered orally once daily. For some patients, treatment may be initiated at 800 mg once daily if the need for seizure reduction outweighs an increased risk of adverse reactions during initiation [see Adverse Reactions (6. 1)] Pediatric Patients (4 to 17 Years of Age) In pediatric patients 4 to 17 years of age, the recommended dosing regimen is dependent upon body weight and is administered orally once daily. The recommended initial dosage of eslicarbazepine acetate tablets is shown in Table 1. Dosage should be increased based on clinical response and tolerability, no more frequently than once per week. Titration increments should not exceed those shown in Table 1. The daily maintenance dosage should not exceed the maintenance dosage for each body weight range shown in Table 1. Table 1: Eslicarbazepine Acetate Tablets Once Daily Dosage Schedule for Pediatric Patients 4 to 17 Years of Age Some adverse reactions occur more frequently when patients take eslicarbazepine acetate tablets adjunctively with carbamazepine [see Warnings and Precautions (5. However, carbamazepine reduces the plasma concentration of eslicarbazepine [see Drug Interactions (7. When eslicarbazepine acetate tablets and carbamazepine are taken concomitantly, the dose of eslicarbazepine acetate tablets or carbamazepine may need to be adjusted based on efficacy and tolerability. For patients taking other enzyme-inducing AEDs (i. , phenobarbital, phenytoin, and primidone), higher doses of eslicarbazepine acetate tablets may be needed [see Drug Interactions (7. Eslicarbazepine acetate tablets should not be taken as an adjunctive therapy with oxcarbazepine. In patients with moderate and severe renal impairment (i. , creatinine clearance < 50 mL/min), the initial, titration, and maintenance dosages should generally be reduced by 50%. Titration and maintenance dosages may be adjusted according to clinical response [see Use in Specific Populations (8. 6) and Clinical Pharmacology (12. Dose adjustments are not required in patients with mild to moderate hepatic impairment. Use of eslicarbazepine acetate tablets in patients with severe hepatic impairment has not been studied, and use in these patients is not recommended [see Use in Specific Populations (8. 7) and Clinical Pharmacology (12. When discontinuing eslicarbazepine acetate tablets, reduce the dosage gradually and avoid abrupt discontinuation in order to minimize the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions (5. image description.

The following adverse reactions are described in more detail in the Warnings and Precautions Suicidal Behavior and Ideation [see Warnings and Precautions ( 5. 1 Serious Dermatologic Reactions [see Warnings and Precautions ( 5. 2 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions ( 5. 3 Anaphylactic Reactions and Angioedema [see Warnings and Precautions ( 5. 4 Hyponatremia [see Warnings and Precautions ( 5. 5 Neurological Adverse Reactions [see Warnings and Precautions ( 5. 6 Drug Induced Liver Injury [see Warnings and Precautions ( 5. 8 Abnormal Thyroid Function Tests [see Warnings and Precautions ( 5. 9 Pancytopenia, Agranulocytosis, and Leukopenia [see Warnings and Precautions ( 5. 10 Most common adverse reactions in adult patients receiving eslicarbazepine acetate tablets (>= 4% and >= 2% greater than placebo): dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor. 1 Adverse reactions in pediatric patients are similar to those seen in adult patients. To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. , at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Patients In monotherapy trials in patients with partial-onset seizures [Study 1 and Study 2, see Clinical Studies (14. 1) , Monotherapy Historical Control Trials In the monotherapy epilepsy trials (Study 1 and Study 2), 13% of patients randomized to receive eslicarbazepine acetate at the recommended doses of 1,200 mg and 1,600 mg once daily discontinued from the trials as a result of an adverse event. The adverse reaction most commonly (>= 1% on eslicarbazepine acetate) leading to discontinuation was hyponatremia. Adverse reactions observed in these studies were generally similar to those observed and attributed to drug in adjunctive placebo-controlled studies. Because these studies did not include a placebo control group, causality could not be established. Dizziness, nausea, somnolence, and fatigue were all reported at lower incidences during the AED Withdrawal Phase and Monotherapy Phase compared with the Titration Phase. Adjunctive Therapy Controlled Trials In the controlled adjunctive therapy epilepsy trials (Study 3, Study 4, and Study 5) , The most frequently reported adverse reactions in patients receiving eslicarbazepine acetate at doses of 800 mg or 1,200 mg (>= 4% and >= 2% greater than placebo) were dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor. Table 4 gives the incidence of adverse reactions that occurred in >= 2% of subjects with partial-onset seizures in any eslicarbazepine acetate treatment group and for which the incidence was greater than placebo during the controlled clinical trials. Adverse reactions during titration were less frequent for patients who began therapy at an initial dose of 400 mg for 1 week and then increased to 800 mg compared to patients who initiated therapy at 800 mg. Table 4: Adverse Reactions Incidence in Pooled Controlled Clinical Trials of Adjunctive Therapy in Adults (Events >= 2% of Patients in the Eslicarbazepine Acetate 800 mg or 1,200 mg Dose Group and More Frequent Than in the Placebo Group) Placebo Eslicarbazepine Acetate 800 mg 1,200 mg (N=426) % (N=415) % (N=410) % Ear and labyrinth disorders < 1 2 6 Eye disorders 2 9 11 Gastrointestinal disorders 5 10 16 General disorders and administration site conditions 4 4 7 Infections and Infestations 1 2 2 Injury, poisoning and procedural 1 3 1 Metabolism and nutrition disorders < 1 2 2 Nervous system disorders 9 20 28 Psychiatric disorders 2 1 3 Respiratory, thoracic and mediastinal disorders 1 2 1 Skin and subcutaneous tissue disorders 1 1 3 Vascular disorders 1 1 2 Pediatric Patients (4 to 17 Years of Age) Clinical studies of pediatric patients 4 to 17 years of age were conducted which support the safety and tolerability of eslicarbazepine acetate for the treatment of partial-onset seizures. Across studies in pediatric patients with partial-onset seizures, 393 patients ages 4 to 17 years received eslicarbazepine acetate, of whom 265 received eslicarbazepine acetate for at least 1 year. Adverse reactions reported in clinical studies of pediatric patients 4 to 17 years of age were similar to those seen in adult patients. Other Adverse Reactions with Eslicarbazepine Acetate Use Compared to placebo, eslicarbazepine acetate use was associated with slightly higher frequencies of decreases in hemoglobin and hematocrit, increases in total cholesterol, triglycerides, and LDL, and increases in creatine phosphokinase. Adverse Reactions Based on Gender and Race No significant gender differences were noted in the incidence of adverse reactions. Although there were few non-Caucasian patients, no differences in the incidences of adverse reactions compared to Caucasian patients were observed. The following adverse reactions have been identified during postapproval use of eslicarbazepine acetate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Hematologic and Lymphatic Systems: leukopenia, agranulocytosis, thrombocytopenia, megaloblastic anemia, and pancytopenia [see Warnings and Precautions (5. 10)] Metabolism and Nutrition Disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH) [see Warnings and Precautions (5.

Eslicarbazepine acetate tablets are contraindicated in patients with a hypersensitivity to eslicarbazepine acetate or oxcarbazepine [see Warnings and Precautions (5. Hypersensitivity to eslicarbazepine acetate or oxcarbazepine.

Pregnancy: Based on animal data, may cause fetal harm. 1 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as eslicarbazepine acetate, during pregnancy. Encourage women who are taking eslicarbazepine acetate during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www. aedpregnancyregistry. Risk Summary Limited available data with eslicarbazepine acetate use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. In oral studies conducted in pregnant mice, rats, and rabbits, eslicarbazepine acetate demonstrated developmental toxicity, including increased incidence of malformations (mice), embryolethality (rats), and fetal growth retardation (all species), at clinically relevant doses (see Data). general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data When eslicarbazepine acetate was orally administered (150, 350, 650 mg/kg/day) to pregnant mice throughout organogenesis, increased incidences of fetal malformations was observed at all doses and fetal growth retardation was observed at the mid and high doses. A no-effect dose for adverse developmental effects was not identified. At the lowest dose tested, plasma eslicarbazepine exposure (Cmax, AUC) is less than that in humans at the maximum recommended human dose (MRHD, 1,600 mg/day). Oral administration of eslicarbazepine acetate (40, 160, 320 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in fetal growth retardation and increased incidences of skeletal variations at the mid and high doses. The no-effect dose (40 mg/kg/day) is less than the MRHD on a mg/m 2 Oral administration to pregnant rats (65, 125, 250 mg/kg/day) throughout organogenesis resulted in embryolethality at all doses, increased incidences of skeletal variations at the mid and high doses, and fetal growth retardation at the high dose. The lowest dose tested (65 mg/kg/day) is less than the MRHD on a mg/m 2 When eslicarbazepine acetate was orally administered to female mice during pregnancy and lactation (150, 350, 650 mg/kg/day), the gestation period was prolonged at the highest dose tested. In offspring, a persistent reduction in offspring body weight and delayed physical development and sexual maturation were observed at the mid and high doses. The lowest dose tested (150 mg/kg/day) is less than the MRHD on a mg/m 2 When eslicarbazepine acetate was orally administered (65, 125, 250 mg/kg/day) to rats during pregnancy and lactation, reduced offspring body weight was seen at the mid and high doses. Delayed sexual maturation and a neurological deficit (decreased motor coordination) were observed at the highest dose tested. The no-effect dose for adverse developmental effects (65 mg/kg/day) is less than the MRHD on a mg/m 2 The rat data are of uncertain relevance to humans because of differences in metabolic profile between species. Eslicarbazepine is present in human milk. The effects of eslicarbazepine acetate on the breastfed infant or on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for eslicarbazepine acetate and any potential adverse effects on the breastfed infant from eslicarbazepine acetate or from the underlying maternal condition. Contraception Use of eslicarbazepine acetate with hormonal contraceptives containing ethinylestradiol or levonorgestrel is associated with lower plasma levels of these hormones. Advise women of reproductive potential taking eslicarbazepine acetate who are using a contraceptive containing ethinylestradiol or levonorgestrel to use additional or alternative non-hormonal birth control [see Drug Interactions (7. Infertility Eslicarbazepine acetate was evaluated in rats and mice for potential adverse impact on fertility of the parental and first generation [see Nonclinical Toxicology (13. Safety and effectiveness of eslicarbazepine acetate have been established in the age groups 4 to 17 years. Use of eslicarbazepine acetate in these age groups is supported by evidence from adequate and well-controlled studies of eslicarbazepine acetate in adults with partial-onset seizures, pharmacokinetic data from adult and pediatric patients, and safety data from clinical studies in 393 pediatric patients 4 to 17 years of age [see Adverse Reactions (6. 1) and Clinical Pharmacology (12. 3)] Safety and effectiveness in pediatric patients below the age of 4 years have not been established. Animal Data In a juvenile animal study in which eslicarbazepine acetate (40, 80, 160 mg/kg/day) was orally administered to young dogs for 10 months starting on postnatal day 21, adverse effects on bone growth (decreased bone mineral content and density) were seen in females at all doses at the end of the dosing period, but not at the end of a 2month recovery period. Convulsions were seen at the highest dose tested. A no-effect dose for adverse effects in juvenile dogs was not identified. The lowest dose tested is less than the maximum recommended pediatric dose (1,200 mg/day) on a body surface area (mg/m 2 A separate juvenile animal study was conducted to assess possible adverse effects on the immune system. Eslicarbazepine acetate (10, 40, 80 mg/kg/day) was orally administered to young dogs for 17 weeks starting on postnatal day 21. No effects on the immune system were observed. There were insufficient numbers of patients >= 65 years old enrolled in the controlled adjunctive epilepsy trials (N=15) to determine the efficacy of eslicarbazepine acetate in this patient population. The pharmacokinetics of eslicarbazepine acetate were evaluated in elderly healthy subjects (N=12) (Figure 3). Although the pharmacokinetics of eslicarbazepine are not affected by age independently, dose selection should take in consideration the greater frequency of renal impairment and other concomitant medical conditions and drug therapies in the elderly patient. Dose adjustment is necessary if CrCl is < 50 mL/min [see Clinical Pharmacology (12. Clearance of eslicarbazepine is decreased in patients with impaired renal function and is correlated with creatinine clearance. Dosage adjustment is necessary in patients with CrCl < 50 mL/min (Figure 3) [see Dosage and Administration (2. 4) and Clinical Pharmacology (12. Dose adjustments are not required in patients with mild to moderate hepatic impairment (Figure 3). Use of eslicarbazepine acetate in patients with severe hepatic impairment has not been evaluated, and use in these patients is not recommended [see Clinical Pharmacology (12.

Carbamazepine: May need dose adjustment for eslicarbazepine acetate tablets or carbamazepine. 1 Phenytoin: Higher dosage of eslicarbazepine acetate tablets may be necessary and dose adjustment may be needed for phenytoin. 2 Phenobarbital or Primidone: Higher dosage of eslicarbazepine acetate tablets may be necessary. 1 Hormonal Contraceptives: Eslicarbazepine acetate tablets may decrease the effectiveness of hormonal contraceptives. 3 Several AEDs (e. , carbamazepine, phenobarbital, phenytoin, and primidone) can induce enzymes that metabolize eslicarbazepine acetate and can cause decreased plasma concentrations of eslicarbazepine [see Clinical Pharmacology (12. 3)] [see Dosage and Administration (2. Eslicarbazepine acetate can inhibit CYP2C19, which can cause increased plasma concentrations of drugs that are metabolized by this isoenzyme (e. , phenytoin, clobazam, and omeprazole) [see Clinical Pharmacology (12. In vivo [see Clinical Pharmacology (12. Because concomitant use of eslicarbazepine acetate and ethinylestradiol and levonorgestrel is associated with lower plasma levels of these hormones, females of reproductive potential should use additional or alternative non-hormonal birth control.

REFERENCES
French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the treatment of epilepsy.">OVERDOSAGE
Symptoms of overdose are consistent with the known adverse reactions of eslicarbazepine acetate and include hyponatremia (sometimes severe), dizziness, nausea, vomiting, somnolence, euphoria, oral paraesthesia, ataxia, walking difficulties, and diplopia. The maximum dosage studied in open-label adult monotherapy treatment following withdrawal of concomitant AEDs was 2,400 mg once daily. There is no specific antidote for overdose with eslicarbazepine acetate. Symptomatic and supportive treatment should be administered as appropriate. Removal of the drug by gastric lavage and/or inactivation by administering activated charcoal should be considered. Standard hemodialysis procedures result in partial clearance of eslicarbazepine acetate. Hemodialysis may be considered based on the patient''s clinical state or in patients with significant renal impairment.
NONCLINICAL TOXICOLOGY
Carcinogenesis In a two-year carcinogenicity study in mice, eslicarbazepine acetate was administered orally at doses of 100, 250, and 600 mg/kg/day. An increase in the incidence of hepatocellular adenomas and carcinomas was observed at 250 and 600 mg/kg/day in males and at 600 mg/kg/day in females. The dose not associated with an increase in tumors (100 mg/kg/day) is less than the MRHD (1,600 mg/day for monotherapy) on a mg/m 2 Mutagenesis Eslicarbazepine acetate and eslicarbazepine were not mutagenic in the in vitro in vitro in vitro tk in vivo Impairment of Fertility When eslicarbazepine acetate (150, 350, and 650 mg/kg/day) was orally administered to male and female mice prior to and throughout the mating period, and continuing in females to gestation day 6, there was an increase in embryolethality at all doses. The lowest dose tested is less than the MRHD on a mg/m2 basis. When eslicarbazepine acetate (65, 125, 250 mg/kg/day) was orally administered to male and female rats prior to and throughout the mating period, and continuing in females to implantation, lengthening of the estrus cycle was observed at the highest dose tested. The data in rats are of uncertain relevance to humans because of differences in metabolic profile between species.
CLINICAL STUDIES
The effectiveness of eslicarbazepine acetate as monotherapy for partial-onset seizures was established in two identical, dose-blinded historical control trials in a total of 365 patients with epilepsy (Study 1 and Study 2). In these trials, patients were randomized in a 2:1 ratio to receive either eslicarbazepine acetate 1,600 mg or 1,200 mg once daily, and their responses were compared to those of a historical control group. The historical control consisted of a pooled analysis of the control groups from 8 trials of similar design, which utilized a subtherapeutic dose of an AED as a comparator. Statistical superiority to the historical control was considered to be demonstrated if the upper limit from a 2-sided 95% confidence interval for the percentage of patients meeting exit criteria in patients receiving eslicarbazepine acetate remained below the lower 95% prediction interval of 65% derived from the historical control data. In Study 1 and Study 2, patients >=16 years of age experienced at least 4 seizures during the baseline period with no 28-day seizure free period while receiving 1 or 2 AEDs (both could not be sodium-channel blocking drugs, and at least one AED was limited to 2/3 of a typical dose). Eslicarbazepine acetate was titrated over a 1-to 2-week period followed by the gradual withdrawal of the background AED over a 6-week period, followed by a 10-week monotherapy period. The exit criteria were one or more of the following: (1) an episode of status epilepticus, (2) emergence of a generalized tonic-clonic seizure in patients who had not had one in the past 6 months, (3) doubling of average monthly seizure count during any 28 consecutive days, (4) doubling of highest consecutive 2-day seizure frequency during the entire treatment phase, or (5) worsening of seizure severity considered by the investigator to require intervention. The primary endpoint was the cumulative 112-day exit rate in the efficacy population. Additionally, in Studies 1 and 2, if the discontinuation rate exceeded 10%, patients were randomly reassigned to be counted as exits. The most commonly used baseline AEDs were carbamazepine, levetiracetam, valproic acid, and lamotrigine. Oxcarbazepine was used as a baseline AED in 6. 6% of patients. In Study 1, the Kaplan-Meier (K-M) estimate of the percentage of patients meeting at least 1 exit criterion was 29% (95% CI: 21%, 38%) in the 1,600 mg group and 44% (95% CI 33%, 58%) in the 1,200 mg group. In Study 2, the K-M estimate of the percentage of patients meeting at least 1 exit criterion was 13% (95% CI: 8%, 22%) in the 1600 mg group and 16% (95% CI: 8%, 29%) in the 1,200 mg group. The upper limit of the 2-sided 95%CI of both doses in both trials were below the threshold of 65% derived from the historical control data, meeting the pre-specified criteria for efficacy (see Figure 4). Figure 4: Kaplan-Meier Estimates of Cumulative 112-Day Exit Rates for Studies 1 and 2 The efficacy of eslicarbazepine acetate as adjunctive therapy in partial-onset seizures was established in three randomized, double-blind, placebo-controlled, multicenter trials in adult patients with epilepsy (Study 3, Study 4, and Study 5). Patients enrolled had partial-onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant AEDs. During an 8-week baseline period, patients were required to have an average of >= 4 partial-onset seizures per 28 days with no seizure-free period exceeding 21 days. In these three trials, patients had a median duration of epilepsy of 19 years and a median baseline seizure frequency of 8 seizures per 28 days. Two-thirds (69%) of subjects used 2 concomitant AEDs and 28% used 1 concomitant AED. The most commonly used AEDs were carbamazepine (50%), lamotrigine (24%), valproic acid (21%), and levetiracetam (18%). Oxcarbazepine was not allowed as a concomitant AED. Studies 3 and 4 compared dosages of eslicarbazepine acetate 400, 800, and 1,200 mg once daily with placebo. Study 5 compared dosages of eslicarbazepine acetate 800 and 1,200 mg once daily with placebo. In all three trials, following an 8 week Baseline Phase, which established a baseline seizure frequency, subjects were randomized to a treatment arm. Patients entered a treatment period consisting of an initial titration phase (2 weeks), and a subsequent maintenance phase (12 weeks). The specific titration schedule differed amongst the three studies. Thus, patients were started on a daily dose of 400 mg or 800 mg and subsequently increased by 400 mg/day following one or two weeks, until the final daily target dose was achieved. The standardized seizure frequency during the Maintenance Phase over 28 days was the primary efficacy endpoint in all three trials. Table 5 presents the results for the primary endpoint, as well as the secondary endpoint of percent reduction from baseline in seizure frequency. The eslicarbazepine acetate treatment at 400 mg/day was studied in Studies 3 and 4 and did not show significant treatment effect. A statistically significant effect was observed with eslicarbazepine acetate treatment at doses of 800 mg/day in Studies 3 and 4, but not in Study 5, and at doses of 1,200 mg/day in all 3 studies. Table 5: Standardized Seizure Frequency During the Maintenance Phase Over 28 Days and PercentReduction from Baseline in Seizure Frequency *statistically significant compared to placebo Placebo Eslicarbazepine Acetate 800 mg 1,200 mg Study 3 N 95 88 87 Seizure Frequency (LS Mean seizures per 28 days) 6. 3 Median Percent Reduction from -15 -36 -39 Study 4 N 99 87 81 Seizure Frequency (LS Mean seizures per 28 days) 8. 6 Median Percent Reduction from -6 -33 -28 Study 5 N 212 200 184 Seizure Frequency (LS Mean seizures per 28 days) 7. 0 Median Percent Reduction from -22 -30 -36 Figure 5 shows changes from baseline in the 28-day total partial seizure frequency by category of reduction in seizure frequency from baseline for patients treated with eslicarbazepine acetate and placebo in an integrated analysis across the three clinical trials. Patients in whom the seizure frequency increased are shown to the left as "Worse. " Patients in whom the seizure frequency decreased are shown in four categories. Figure 5: Proportion of Patients by Category of Seizure Reduction for Eslicarbazepine Acetate and Placebo Across All Three Double-blind Trials image description image description.
REFERENCES
French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the treatment of epilepsy.

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