ESLICARBAZEPINE ACETATE- eslicarbazepine acetate_tablet

Eslicarbazepine acetate is 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 tablets 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 is 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 tablets. Peak plasma concentrations (C max Distribution The binding of eslicarbazepine to plasma proteins is relatively low (<40%) and independent of concentration. In vitro Metabolism Eslicarbazepine acetate is 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. 6 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 tablets 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 tablets [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 <30 mL/min) in comparison to the healthy subjects (CrCl >80 mL/min). Dosage adjustment is recommended in patients with creatinine clearance below 50 mL/min [see Dosage and Administration ( 2. 6 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 tablets. No dose adjustment is recommended in patients with mild to moderate liver impairment. The pharmacokinetics of eslicarbazepine acetate tablets 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 Figure 2 Figure 3 Figure 4 Figure 5.

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. 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 tablet 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. 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 tablet 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 Bo d y Weight Range Initial and Maximum Titration Increment Dosage (mg/day) Ma in tenance Dosage (mg/day) 11 to 21 kg 200 400 to 600 22 to 31 kg 300 500 to 800 32 to 38 kg 300 600 to 900 more than 38 kg 400 800 to 1,200 Some adverse reactions occur more frequently when patients take eslicarbazepine acetate tablets adjunctively with carbamazepine [see Warnings and Precautions ( 5. 6 [see Drug Interactions ( 7. 1 [see Drug Interactions ( 7. 1 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. 3 Dose adjustments are not required in patients with mild to moderate hepatic impairment. Use of eslicarbazepine acetate in patients with severe hepatic impairment has not been studied, and use in these patients is not recommended [see Use in Specific Populations ( 8. 3 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.

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 Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www. gov/medwatch 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 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 tablets 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 tablets 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 <1 2 6 Eye disorders Diplopia 2 9 11 Blurred vision 1 6 5 Visual impairment 1 2 1 Gastrointestinal disorders Nausea 5 10 16 Vomiting 3 6 10 Diarrhea 3 4 2 Constipation 1 2 2 Abdominal pain 1 2 2 Gastritis <1 2 <1 General disorders and administration site conditions Fatigue 4 4 7 Asthenia 2 2 3 Gait disturbance <1 2 2 Peripheral edema 1 2 1 Infections and Infestations Urinary tract infections 1 2 2 Injury, poisoning and procedural 1 3 1 Metabolism and nutrition disorders <1 2 2 Nervous system disorders Dizziness 9 20 28 Somnolence 8 11 18 Headache 9 13 15 Ataxia 2 4 6 Balance disorder <1 3 3 Tremor 1 2 4 Dysarthria 0 1 2 Memory impairment <1 1 2 Nystagmus <1 1 2 Psychiatric disorders Depression 2 1 3 Insomnia 1 2 2 Respiratory, thoracic and mediastinal 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 tablets, of whom 265 received eslicarbazepine acetate tablets 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 eslicarbazepinenacetate tablets. 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. 4 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 tablets 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 tablets 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 (C max 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 tablets 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 tablets and any potential adverse effects on the breastfed infant from eslicarbazepine acetate tablets or from the underlying maternal condition. Contraception Use of eslicarbazepine acetate tablets 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 Safety and effectiveness of eslicarbazepine acetate tablets have been established in the age groups 4 to 17 years. Use of eslicarbazepine acetate tablets in these age groups is supported by evidence from adequate and well-controlled studies of eslicarbazepine acetate tablets 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. 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 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 tablets in this patient population. The pharmacokinetics of eslicarbazepine acetate tablets 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 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. 3 Dose adjustments are not required in patients with mild to moderate hepatic impairment (Figure 1). Use of eslicarbazepine acetate tablets 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 or carbamazepine. 1 Phenytoin: Higher dosage of eslicarbazepine acetate may be necessary and dose adjustment may be needed for phenytoin. 2 Phenobarbital or Primidone: Higher dosage of eslicarbazepine acetate may be necessary. 1 Hormonal Contraceptives: Eslicarbazepine acetate 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. 4 Eslicarbazepine acetate tablets 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. 3 In vivo [see Clinical Pharmacology ( 12. 3 Because concomitant use of eslicarbazepine acetate tablets 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.
MEDICATION GUIDE
Dispense with Medication Guide available at: "www. com/eslicarbazepineacetab-mg. pdf" Eslicarbazepine Acetate Tablets (es-li-kar-BAZ-e-peen) What is the most important information I should know about eslicarbazepine acetate tablets? Do not stop taking eslicarbazepine acetate tablets without first talking to your healthcare provider. Stopping eslicarbazepine acetate tablets suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy may cause seizures that will not stop (status epilepticus). Like other antiepileptic drugs, eslicarbazepine acetate tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying attempt to commit suicide new or worse depression new or worse anxiety feeling agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Suicidal thoughts or actions may be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. Eslicarbazepine acetate tablets may cause allergic reactions or serious problems which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions. Call your healthcare provider right away if you have any of the following: swelling of your face, eyes, lips, or tongue trouble swallowing or breathing a skin rash hives fever, swollen glands, or sore throat that do not go away or come and go painful sores in the mouth or around your eyes yellowing of your skin or eyes unusual bruising or bleeding severe fatigue or weakness severe muscle pain frequent infections or infections that do not go away Eslicarbazepine acetate tablets may cause the level of sodium in your blood to be low. Symptoms of low blood sodium include: nausea tiredness, lack of energy irritability confusion muscle weakness or muscle spasms more frequent or more severe seizures Some medicines can also cause low sodium in your blood. Be sure to tell your healthcare provider about all the other medicines that you are taking. What is eslicarbazepine acetate tablet? Eslicarbazepine acetate tablet is a prescription medicine used to treat partial-onset seizures. It is not known if eslicarbazepine acetate tablets is safe and effective in children under 4 years of age. Who should not take eslicarbazepine acetate tablets? Do not take eslicarbazepine acetate tablets if you are allergic to eslicarbazepine acetate, any of the other ingredients in eslicarbazepine acetate tablets, or oxcarbazepine. See the end of this Medication Guide for a complete list of ingredients in eslicarbazepine acetate tablets. What should I tell my healthcare provider before taking eslicarbazepine acetate tablets? Before taking eslicarbazepine acetate tablets, tell your healthcare provider about all your medical conditions, including if you: have or have had suicidal thoughts or actions, depression or mood problems have liver, kidney, or blood problems are allergic to oxcarbazepine. Some people who are allergic to oxcarbazepine may also be allergic to eslicarbazepine acetate tablets. use birth control medicine. Eslicarbazepine acetate tablets may cause your birth control medicine to be less effective. Talk to your healthcare provider about the best birth control method to use. are pregnant or plan to become pregnant. Eslicarbazepine acetate tablets may harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking eslicarbazepine acetate tablets. You and your healthcare provider will decide if you should take eslicarbazepine acetate tablets while you are pregnant. If you become pregnant while taking eslicarbazepine acetate tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy. You can enroll in this registry by calling 1-888-233-2334. are breastfeeding or plan to breastfeed. Eslicarbazepine acetate passes into breast milk. You and your healthcare provider should discuss whether you should take eslicarbazepine acetate tablets or breastfeed. Tell your healthcare provider about all the medicines you take, Taking eslicarbazepine acetate tablets with certain other medicines may cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Especially tell your healthcare provider if you take: oxcarbazepine carbamazepine simvastatin omeprazole phenobarbital phenytoin birth control medicine rosuvastatin clobazam primidone Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take eslicarbazepine acetate tablets? Take eslicarbazepine acetate tablets exactly as your healthcare provider tells you to take it. Do not stop taking eslicarbazepine acetate tablets without talking to your healthcare provider. Stopping eslicarbazepine acetate tablets suddenly can cause serious problems, including seizures that will not stop (status epilepticus). Your healthcare provider may change your dose. Your healthcare provider will tell you how much eslicarbazepine acetate tablets to take. Eslicarbazepine acetate tablets can be taken with or without food. eslicarbazepine acetate tablets can be taken as a whole tablet or crushed. If you take too much eslicarbazepine acetate tablets, call your healthcare provider or go to the nearest hospital emergency room right away. Talk with your healthcare provider about what you should do if you miss a dose. What should I avoid while taking eslicarbazepine acetate tablets? Do not drive, operate heavy machinery, or do dangerous activities until you know how eslicarbazepine acetate tablets affects you. Eslicarbazepine acetate tablets may slow your thinking and motor skills. What are the possible side effects of eslicarbazepine acetate tablets? See "What is the most important information I should know about eslicarbazepine acetate tablets?" Eslicarbazepine acetate tablets may cause other serious side effects including: Nervous system problems dizziness trouble walking or with coordination feeling sleepy and tired trouble concentrating vision problems Liver problems yellowing of your skin or the whites of your eyes nausea or vomiting loss of appetite stomach pain dark urine Get medical help right away if you have any of the symptoms listed above or listed in " What is the most important information I should know about eslicarbazepine acetate tablets? " The most common side effects of eslicarbazepine acetate tablets include: dizziness sleepiness nausea headache double vision vomiting feeling tired blurred vision shakiness problems with coordination Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of eslicarbazepine acetate tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store eslicarbazepine acetate tablets? Store at 25 ° ° ° ° ° ° Safely throw away medicine that is out of date or no longer needed. Keep eslicarbazepine acetate tablets and all medicines out of reach of children. What are the ingredients in eslicarbazepine acetate tablets? Active ingredient Inactive ingredients General information about the safe and effective use of eslicarbazepine acetate tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use eslicarbazepine acetate tablets for a condition for which it was not prescribed. Do not give eslicarbazepine acetate tablets to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about eslicarbazepine acetate tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about eslicarbazepine acetate tablets that is written for health professionals. For more information about eslicarbazepine acetate tablets, call Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or visit our website at www. lupinpharmaceuticals. Lupin and the Manufactured for: Lupin Pharmaceuticals, Inc. Naples, FL 34108, United States Manufactured by: Lupin Limited Goa 403722, India Revised: February 2025 ID#: 279595 This Medication Guide has been approved by the U. Food and Drug Administration.">OVERDOSAGE
Symptoms of overdose are consistent with the known adverse reactions of eslicarbazepine acetate tablets 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 tablets. 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 tablets. 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 Ames assay. In in vitro 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/m 2 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 tablets 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 methodology is described in a publication by French et al. [see References ( 15 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 tablets were 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 1,600 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 tablets 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 periodconsisting 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 Percent Reduction from Baseline in Seizure Frequency * P l acebo Eslicarbazepine acetate tablets 800 mg 1,200 mg S tudy 3 N 95 88 87 Seizure Frequency (LS Mean seizures per 28 days) 6. 3 (p-value) (0. 001 * Median Percent Reduction from Baseline in Seizure Frequency (%) -15 -36 -39 S tudy 4 N 99 87 81 Seizure Frequency (LS Mean seizures 8. 6 per 28 days) (p-value) (0. 042 * Median Percent Reduction from Baseline in Seizure Frequency (%) -6 -33 -28 S tudy 5 N 212 200 184 Seizure Frequency (LS Mean seizures 7. 0 per 28 days) (p-value) (0. 004 * Median Percent Reduction from Baseline in Seizure Frequency (%) -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 Figure 6 Figure 7.
REFERENCES
French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the treatment of epilepsy.
MEDICATION GUIDE
Dispense with Medication Guide available at: "www. com/eslicarbazepineacetab-mg. pdf" Eslicarbazepine Acetate Tablets (es-li-kar-BAZ-e-peen) What is the most important information I should know about eslicarbazepine acetate tablets? Do not stop taking eslicarbazepine acetate tablets without first talking to your healthcare provider. Stopping eslicarbazepine acetate tablets suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy may cause seizures that will not stop (status epilepticus). Like other antiepileptic drugs, eslicarbazepine acetate tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying attempt to commit suicide new or worse depression new or worse anxiety feeling agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Suicidal thoughts or actions may be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. Eslicarbazepine acetate tablets may cause allergic reactions or serious problems which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions. Call your healthcare provider right away if you have any of the following: swelling of your face, eyes, lips, or tongue trouble swallowing or breathing a skin rash hives fever, swollen glands, or sore throat that do not go away or come and go painful sores in the mouth or around your eyes yellowing of your skin or eyes unusual bruising or bleeding severe fatigue or weakness severe muscle pain frequent infections or infections that do not go away Eslicarbazepine acetate tablets may cause the level of sodium in your blood to be low. Symptoms of low blood sodium include: nausea tiredness, lack of energy irritability confusion muscle weakness or muscle spasms more frequent or more severe seizures Some medicines can also cause low sodium in your blood. Be sure to tell your healthcare provider about all the other medicines that you are taking. What is eslicarbazepine acetate tablet? Eslicarbazepine acetate tablet is a prescription medicine used to treat partial-onset seizures. It is not known if eslicarbazepine acetate tablets is safe and effective in children under 4 years of age. Who should not take eslicarbazepine acetate tablets? Do not take eslicarbazepine acetate tablets if you are allergic to eslicarbazepine acetate, any of the other ingredients in eslicarbazepine acetate tablets, or oxcarbazepine. See the end of this Medication Guide for a complete list of ingredients in eslicarbazepine acetate tablets. What should I tell my healthcare provider before taking eslicarbazepine acetate tablets? Before taking eslicarbazepine acetate tablets, tell your healthcare provider about all your medical conditions, including if you: have or have had suicidal thoughts or actions, depression or mood problems have liver, kidney, or blood problems are allergic to oxcarbazepine. Some people who are allergic to oxcarbazepine may also be allergic to eslicarbazepine acetate tablets. use birth control medicine. Eslicarbazepine acetate tablets may cause your birth control medicine to be less effective. Talk to your healthcare provider about the best birth control method to use. are pregnant or plan to become pregnant. Eslicarbazepine acetate tablets may harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking eslicarbazepine acetate tablets. You and your healthcare provider will decide if you should take eslicarbazepine acetate tablets while you are pregnant. If you become pregnant while taking eslicarbazepine acetate tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy. You can enroll in this registry by calling 1-888-233-2334. are breastfeeding or plan to breastfeed. Eslicarbazepine acetate passes into breast milk. You and your healthcare provider should discuss whether you should take eslicarbazepine acetate tablets or breastfeed. Tell your healthcare provider about all the medicines you take, Taking eslicarbazepine acetate tablets with certain other medicines may cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Especially tell your healthcare provider if you take: oxcarbazepine carbamazepine simvastatin omeprazole phenobarbital phenytoin birth control medicine rosuvastatin clobazam primidone Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take eslicarbazepine acetate tablets? Take eslicarbazepine acetate tablets exactly as your healthcare provider tells you to take it. Do not stop taking eslicarbazepine acetate tablets without talking to your healthcare provider. Stopping eslicarbazepine acetate tablets suddenly can cause serious problems, including seizures that will not stop (status epilepticus). Your healthcare provider may change your dose. Your healthcare provider will tell you how much eslicarbazepine acetate tablets to take. Eslicarbazepine acetate tablets can be taken with or without food. eslicarbazepine acetate tablets can be taken as a whole tablet or crushed. If you take too much eslicarbazepine acetate tablets, call your healthcare provider or go to the nearest hospital emergency room right away. Talk with your healthcare provider about what you should do if you miss a dose. What should I avoid while taking eslicarbazepine acetate tablets? Do not drive, operate heavy machinery, or do dangerous activities until you know how eslicarbazepine acetate tablets affects you. Eslicarbazepine acetate tablets may slow your thinking and motor skills. What are the possible side effects of eslicarbazepine acetate tablets? See "What is the most important information I should know about eslicarbazepine acetate tablets?" Eslicarbazepine acetate tablets may cause other serious side effects including: Nervous system problems dizziness trouble walking or with coordination feeling sleepy and tired trouble concentrating vision problems Liver problems yellowing of your skin or the whites of your eyes nausea or vomiting loss of appetite stomach pain dark urine Get medical help right away if you have any of the symptoms listed above or listed in " What is the most important information I should know about eslicarbazepine acetate tablets? " The most common side effects of eslicarbazepine acetate tablets include: dizziness sleepiness nausea headache double vision vomiting feeling tired blurred vision shakiness problems with coordination Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of eslicarbazepine acetate tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store eslicarbazepine acetate tablets? Store at 25 ° ° ° ° ° ° Safely throw away medicine that is out of date or no longer needed. Keep eslicarbazepine acetate tablets and all medicines out of reach of children. What are the ingredients in eslicarbazepine acetate tablets? Active ingredient Inactive ingredients General information about the safe and effective use of eslicarbazepine acetate tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use eslicarbazepine acetate tablets for a condition for which it was not prescribed. Do not give eslicarbazepine acetate tablets to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about eslicarbazepine acetate tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about eslicarbazepine acetate tablets that is written for health professionals. For more information about eslicarbazepine acetate tablets, call Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or visit our website at www. lupinpharmaceuticals. Lupin and the Manufactured for: Lupin Pharmaceuticals, Inc. Naples, FL 34108, United States Manufactured by: Lupin Limited Goa 403722, India Revised: February 2025 ID#: 279595 This Medication Guide has been approved by the U. Food and Drug Administration.

Lupin Pharmaceuticals, Inc.

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