Eslicarbazepine

5 WARNINGS AND PRECAUTIONS • Suicidal Behavior and Ideation: Monitor for suicidal thoughts or behavior. ( 5.1 ) • Serious Dermatologic Reactions, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Anaphylactic Reactions and Angioedema: Monitor and discontinue if another cause cannot be established. ( 5.2 , 5.3 , 5.4 ) • Hyponatremia: Monitor sodium levels in patients at risk or patients experiencing hyponatremia symptoms. ( 5.5 ) • Neurological Adverse Reactions: Monitor for dizziness, disturbance in gait and coordination, somnolence, fatigue, cognitive dysfunction, and visual changes. Use caution when driving or operating machinery. ( 5.6 ) • Withdrawal of eslicarbazepine acetate: Withdraw eslicarbazepine acetate gradually to minimize the risk of increased seizure frequency and status epilepticus. ( 2.6 , 5.7 , 8.1 ) • Drug Induced Liver Injury: Discontinue eslicarbazepine acetate tablets in patients with jaundice or evidence of significant liver injury. ( 5.8 ) • Hematologic Adverse Reactions: Consider discontinuing. ( 5.10 ) 5.1 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including eslicarbazepine acetate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono-and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% confidence interval [CI]: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3: Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Differences: Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for epilepsy and psychiatric indications. Anyone considering prescribing eslicarbazepine acetate tablets or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression; any unusual changes in mood or behavior; or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. 5.2 Serious Dermatologic Reactions Serious dermatologic reactions including Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in association with eslicarbazepine acetate use. Serious and sometimes fatal dermatologic reactions, including TEN and SJS, have also been reported in patients using oxcarbazepine or carbamazepine which are chemically related to eslicarbazepine acetate. The reporting rate of these reactions associated with oxcarbazepine use exceeds the background incidence rate estimates by a factor of 3-to 10-fold. The reporting rates for eslicarbazepine acetate have not been determined. Risk factors for the development of serious and potentially fatal dermatologic reactions with eslicarbazepine acetate use have not been identified. If a patient develops a dermatologic reaction while taking eslicarbazepine acetate tablets, discontinue eslicarbazepine acetate tablets use, unless the reaction is clearly not drug-related. Patients with a prior dermatologic reaction with oxcarbazepine, carbamazepine, or eslicarbazepine acetate should ordinarily not be treated with eslicarbazepine acetate [see Contraindications ( 4 )]. 5.3 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking eslicarbazepine acetate tablets. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. 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. Eslicarbazepine acetate tablets should be discontinued and not be resumed if an alternative etiology for the signs or symptoms cannot be established. Patients with a prior DRESS reaction with either oxcarbazepine or eslicarbazepine acetate should not be treated with eslicarbazepine acetate tablets [see Contraindications ( 4 )] . 5.4 Anaphylactic Reactions and Angioedema Rare cases of anaphylaxis and angioedema have been reported in patients taking eslicarbazepine acetate tablets. Anaphylaxis and angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with eslicarbazepine acetate, the drug should be discontinued. Patients with a prior anaphylactic-type reaction with either oxcarbazepine or eslicarbazepine acetate should not be treated with eslicarbazepine acetate [see Contraindications ( 4 )]. 5.5 Hyponatremia Clinically significant hyponatremia (sodium 3 times the upper limit of normal) to rare cases with concomitant elevations of total bilirubin (>2 times the upper limit of normal) have been reported with eslicarbazepine acetate use. Baseline evaluations of liver laboratory tests are recommended. 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 tablets should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence). 5.9 Abnormal Thyroid Function Tests Dose-dependent decreases in serum T3 and T4 (free and total) values have been observed in patients taking eslicarbazepine acetate tablets. These changes were not associated with other abnormal thyroid function tests suggesting hypothyroidism. Abnormal thyroid function tests should be clinically evaluated. 5.10 Hematologic Adverse Reactions Rare cases of pancytopenia, agranulocytosis, and leukopenia have been reported during postmarketing use in patients treated with eslicarbazepine acetate. Discontinuation of eslicarbazepine acetate tablets should be considered in patients who develop pancytopenia, agranulocytosis, or leukopenia.

6 ADVERSE REACTIONS The following adverse reactions are described in more detail in the Warnings and Precautions section of the label: • 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 (≥4% and ≥2% greater than placebo): dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor. ( 6.1 ) • Adverse reactions in pediatric patients are similar to those seen in adult patients. To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 ) ], 365 patients received eslicarbazepine acetate, of whom 225 were treated for longer than 12 months and 134 for longer than 24 months. Of the patients in those trials, 95% were between 18 and 65 years old; 48% were male, and 84% were Caucasian. Across controlled and uncontrolled trials in patients receiving adjunctive therapy for partial-onset seizures, 1,195 patients received eslicarbazepine acetate, of whom 586 were treated for longer than 6 months and 462 for longer than 12 months. In the placebo controlled adjunctive therapy trials in patients with partial-onset seizures (Study 3, Study 4 and Study 5), 1,021 patients received eslicarbazepine acetate. Of the patients in those trials, approximately 95% were between 18 and 60 years old, approximately 50% were male, and approximately 80% were Caucasian. 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 rate of discontinuation as a result of any adverse reaction was 14% for the 800 mg dose, 25% for the 1,200 mg dose, and 7% in subjects randomized to placebo. The adverse reactions most commonly (≥1% in any eslicarbazepine acetate treatment group, and greater than placebo) leading to discontinuation, in descending order of frequency, were dizziness, nausea, vomiting, ataxia, diplopia, somnolence, headache, blurred vision, vertigo, asthenia, fatigue, rash, dysarthria, and tremor. 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 Tablets 800 mg or 1,200 mg Dose Group and More Frequent Than in the Placebo Group) Placebo Eslicarbazepine Acetate Tablets 800 mg 1,200 mg (N=426) % (N=415) % (N=410) % Ear and labyrinth disorders Vertigo <1 2 6 Eye disorders Diplopia Blurred vision Visual impairment 2 1 1 9 6 2 11 5 1 Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Abdominal pain Gastritis 5 3 3 1 1 <1 10 6 4 2 2 2 16 10 2 2 2 <1 General disorders and administration site conditions Fatigue Asthenia Gait disturbance Peripheral edema 4 2 <1 1 4 2 2 2 7 3 2 1 Infections and Infestations Urinary tract infections 1 2 2 Injury, poisoning and procedural complications Fall 1 3 1 Metabolism and nutrition disorders Hyponatremia <1 2 2 Nervous system disorders Dizziness Somnolence Headache Ataxia Balance disorder Tremor Dysarthria Memory impairment Nystagmus 9 8 9 2 <1 1 0 <1 <1 20 11 13 4 3 2 1 1 1 28 18 15 6 3 4 2 2 2 Psychiatric disorders Depression Insomnia 2 1 1 2 3 2 Respiratory, thoracic and mediastinal disorders Cough 1 2 1 Skin and subcutaneous tissue disorders Rash 1 1 3 Vascular disorders Hypertension 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. 6.2 Postmarketing Experience 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 ( 5.5 )]

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) 8.1 Pregnancy 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.org. 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). Advise a pregnant woman of the potential risk to a fetus. In the U.S. 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 (C max , 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 basis. 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 basis. 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 basis. 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 basis. The rat data are of uncertain relevance to humans because of differences in metabolic profile between species. 8.2 Lactation 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. 8.3 Females and Males of Reproductive Potential 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 tablets who are using a contraceptive containing ethinylestradiol or levonorgestrel to use additional or alternative non-hormonal birth control [see Drug Interactions ( 7.4 )]. Infertility Eslicarbazepine acetate was evaluated in rats and mice for potential adverse impact on fertility of the parental and first generation [see Nonclinical Toxicology ( 13.1 )] . In a fertility study in male and female mice, adverse developmental outcomes were observed in embryos. In a fertility study in male and female rats, impairment of female fertility by eslicarbazepine acetate was shown. 8.4 Pediatric Use 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 2 month 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 ) basis. 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. 8.5 Geriatric Use 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 1). 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 ( 12.3 )]. 8.6 Patients with Renal Impairment 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 1) [see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )] . 8.7 Patients with Hepatic Impairment Dose adjustments are not required in patients with mild to moderate hepatic impairment (Figure 1). 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 ( 12.3 )] .

8.1 Pregnancy 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.org. 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). Advise a pregnant woman of the potential risk to a fetus. In the U.S. 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 (C max , 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 basis. 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 basis. 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 basis. 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 basis. The rat data are of uncertain relevance to humans because of differences in metabolic profile between species.