healing procedures [30:<16 years of age), statistically significant decreases in WBC and neutrophil counts were seen in patients treated with immediate-release Levetiracetam, as compared to placebo. The mean decreases from baseline in the immediate-release Levetiracetam group were -0.4 10 9 /L and -0.3 10 9 /L, respectively, whereas there were small increases in the placebo group. A significant increase in mean relative lymphocyte counts was observed in 1.7% of patients treated with immediate-release Levetiracetam compared to a decrease of 4% in patients on placebo. In the controlled pediatric trial, a possibly clinically significant abnormal low WBC value was observed in 3% of patients treated with immediate-release Levetiracetam, compared to no patients on placebo. However, there was no apparent difference between treatment groups with respect to neutrophil count. No patient was discontinued secondary to low WBC or neutrophil counts. In the controlled pediatric cognitive and neuropsychological safety study, two subjects (6.1%) in the placebo group and 5 subjects (8.6%) in the immediate-release Levetiracetam-treated group had high eosinophil count values that were possibly clinically significant ( 10% or 0.7X10 9 /L). 5.9 Seizure Control During Pregnancy Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy. This decrease is more pronounced during the third trimester. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy. 6 ADVERSE REACTIONS The following adverse reactions are discussed in more details in other sections of labeling: Behavioral abnormalities and Psychotic Symptoms [ see Warnings and Precautions (5.1) ] Suicidal Behavior And Ideation [ see Warnings and Precautions (5.2) ] Somnolence And Fatigue [ see Warnings and Precautions (5.3) ] Anaphylaxis and Angioedema [see Warnings and Precautions (5.4) ] Serious Dermatological Reactions [ see Warnings and Precautions (5.5) ] Coordination Difficulties [ see Warnings and Precautions (5.6) ] Hematologic Abnormalities [ see Warnings and Precautions (5.8) ] 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. Levetiracetam Extended-release Tablets In the controlled clinical study in patients with partial onset seizures, the most common adverse reactions in patients receiving Levetiracetam Extended-release Tablets in combination with other AEDs, for events with rates greater than placebo, were irritability and somnolence. Table 3 lists adverse reactions that occurred in at least 5% of epilepsy patients receiving Levetiracetam Extended-release Tablets in the placebo-controlled study and were numerically more common than in patients treated with placebo. In this study, either Levetiracetam Extended-release Tablets or placebo was added to concurrent AED therapy. Table 3: Adverse Reactions in the Placebo-Controlled, Add-On Study in Patients Experiencing Partial Onset Seizures Levetiracetam Extended-release Tablets (N=77) % Placebo (N=79) % Influenza 8 4 Somnolence 8 3 Irritability 7 0 Nasopharyngitis 7 5 Dizziness 5 3 Nausea 5 3 Discontinuation or Dose Reduction in the Levetiracetam Extended-release Tablets Controlled Clinical Study In the controlled clinical study, 5% of patients receiving Levetiracetam Extended-release Tablets and 3% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions that resulted in discontinuation and that occurred more frequently in Levetiracetam Extended-release Tablets-treated patients than in placebo-treated patients were asthenia, epilepsy, mouth ulceration, rash and respiratory failure. Each of these adverse reactions led to discontinuation in a Levetiracetam Extended-release Tablets-treated patient and no placebo-treated patients. Immediate-Release Levetiracetam Tablets Table 4 lists the adverse reactions in the controlled studies of immediate-release levetiracetam tablets in adult patients experiencing partial onset seizures. Although the pattern of adverse reactions in the Levetiracetam Extended-release Tablets study seems somewhat different from that seen in partial onset seizure controlled studies for immediate-release Levetiracetam tablets, this is possibly due to the much smaller number of patients in this study compared to the immediate-release tablet studies. The adverse reactions for Levetiracetam Extended-release Tablets are expected to be similar to those seen with immediate-release Levetiracetam tablets. Adults In controlled clinical studies of immediate-release Levetiracetam tablets as adjunctive therapy to other AEDs in adults with partial onset seizures, the most common adverse reactions, for events with rates greater than placebo, were somnolence, asthenia, infection, and dizziness. Table 4 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving immediate-release Levetiracetam tablets in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either immediate-release Levetiracetam tablets or placebo was added to concurrent AED therapy. Table 4: Adverse Reactions in Pooled Placebo-Controlled, Add-On Studies in Adults Experiencing Partial Onset Seizures Levetiracetam (N=769) % Placebo (N=439) % Asthenia 15 9 Somnolence 15 8 Headache 14 13 Infection 13 8 Dizziness 9 4 Pain 7 6 Pharyngitis 6 4 Depression 4 2 Nervousness 4 2 Rhinitis 4 3 Anorexia 3 2 Ataxia 3 1 Vertigo 3 1 Amnesia 2 1 Anxiety 2 1 Cough Increased 2 1 Diplopia 2 1 Emotional Lability 2 0 Hostility 2 1 Paresthesia 2 1 Sinusitis 2 1 Pediatric Patients 4 Years to> <16 Years In a pooled analysis of two controlled pediatric clinical studies in children 4 to 16 years of age with partial onset seizures, the adverse reactions most frequently reported with the use of immediate-release Levetiracetam in combination with other AEDs, and with greater frequency than in patients on placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability. Table 5 lists adverse reactions that occurred in at least 2% of pediatric patients treated with immediate-release Levetiracetam and were more common than in pediatric patients on placebo. In these studies, either immediate-release Levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 5: Adverse Reactions in Pooled Placebo-Controlled, Add-On Studies in Pediatric Patients Ages 4 to 16 Years Experiencing Partial Onset Seizures Levetiracetam (N=165) % Placebo (N=131) % Headache 19 15 Nasopharyngitis 15 12 Vomiting 15 12 Somnolence 13 9 Fatigue 11 5 Aggression 10 5 Abdominal Pain Upper 9 8 Cough 9 5 Nasal Congestion 9 2 Decreased Appetite 8 2 Abnormal Behavior 7 4 Dizziness 7 5 Irritability 7 1 Pharyngolaryngeal Pain 7 4 Diarrhea 6 2 Lethargy 6 5 Insomnia 5 3 Agitation 4 1 Anorexia 4 3 Head Injury 4 0 Constipation 3 1 Contusion 3 1 Depression 3 1 Fall 3 2 Influenza 3 1 Mood Altered 3 1 Affect Lability 2 1 Anxiety 2 1 Arthralgia 2 0 Confusional State 2 0 Conjunctivitis 2 0 Ear Pain 2 1 Gastroenteritis 2 0 Joint Sprain 2 1 Mood Swings 2 1 Neck Pain 2 1 Rhinitis 2 0 Sedation 2 1 In controlled pediatric clinical studies in patients 4-16 years of age, 7% of patients treated with immediate-release Levetiracetam tablets and 9% of patients on placebo discontinued as a result of an adverse event. In addition, the following adverse reactions were seen in other controlled studies of immediate-release Levetiracetam tablets: balance disorder, disturbance in attention, eczema, hyperkinesia, memory impairment, myalgia, personality disorders, pruritus, and blurred vision. Comparison of Gender, Age and Race There are insufficient data for Levetiracetam Extended-release Tablets to support a statement regarding the distribution of adverse reactions by gender, age and race. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of immediate-release Levetiracetam 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. The listing is alphabetized: abnormal liver function test, acute kidney injury, anaphylasix, angioedema, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, and weight loss. Alopecia has been reported with immediate-release Levetiracetam use; recovery was observed in majority of cases where immediate-release Levetiracetam was discontinued. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Roweepra XR levels may decrease during pregnancy [ see Warnings and Precautions (5.9) ]. Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. Roweepra XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral administration of levetiracetam to female rats throughout pregnancy and lactation led to increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses 350 mg/kg/day (equivalent to the maximum recommended human dose of 3,000 mg [MRHD] on a mg/m 2 basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1,800 mg/kg/day (6 times the MRHD on a mg/m 2 basis). The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m 2 basis). There was no overt maternal toxicity at the doses used in this study. Oral administration of levetiracetam to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and increased incidences of minor fetal skeletal abnormalities at doses 600 mg/kg/day (4 times MRHD on a mg/m 2 basis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1,800 mg/kg/day (12 times the MRHD on a mg/m 2 basis). The developmental no effect dose was 200 mg/kg/day (equivalent to the MRHD on a mg/m 2 basis). Maternal toxicity was also observed at 1,800 mg/kg/day. When levetiracetam was administered orally to pregnant rats during the period of organogenesis, fetal weights were decreased and the incidence of fetal skeletal variations was increased at a dose of 3,600 mg/kg/day (12 times the MRHD). 1,200 mg/kg/day (4 times the MRHD) was a developmental no effect dose. There was no evidence of maternal toxicity in this study. Treatment of rats with levetiracetam during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at oral doses of up to 1,800 mg/kg/day (6 times the MRHD on a mg/m 2 basis). Pregnancy Registry To provide information regarding the effects of in utero exposure to Roweepra XR, physicians are advised to recommend that pregnant patients taking Roweepra XR enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by the patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. 8.2 Labor and Delivery The effect of Roweepra XR on labor and delivery in humans is unknown. 8.3 Nursing Mothers Levetiracetam is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Roweepra XR, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients 12 years of age and older has been established based on pharmacokinetic data in adults and adolescents using Levetiracetam Extended-release Tablets and efficacy and safety data in controlled pediatric studies using immediate-release Levetiracetam [ see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ]. A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of immediate-release Levetiracetam as adjunctive therapy in 98 pediatric patients with inadequately controlled partial seizures, ages 4 to 16 years (Levetiracetam N=64; placebo N=34). The target dose of immediate-release Levetiracetam was 60 mg/kg/day. Neurocognitive effects were measured by the Leiter-R Attention and Memory (AM) Battery, which assesses various aspects of a child's memory and attention. Although no substantive differences were observed between the placebo- and Levetiracetam-treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority between the drug and placebo. The Achenbach Child Behavior Checklist (CBCL/6-18), a standardized validated tool used to assess a child's competencies and behavioral/emotional problems, was also assessed in this study. An analysis of the CBCL/6-18 indicated a worsening in aggressive behavior, one of the eight syndrome scores, in patients treated with Levetiracetam [ see Warnings and Precautions (5.1) ]. Studies of levetiracetam in juvenile rats (dosing from day 4 through day 52 of age) and dogs (dosing from week 3 through week 7 of age) at doses of up to 1,800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m 2 basis) did not indicate a potential for age-specific toxicity. 8.5 Geriatric Use There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of Levetiracetam Extended-release Tablets in these patients. It is expected that the safety of Levetiracetam Extended-release Tablets in elderly patients 65 and over would be comparable to the safety observed in clinical studies of immediate-release Levetiracetam tablets. There were 347 subjects in clinical studies of immediate-release Levetiracetam that were 65 and over. No overall differences in safety were observed between these subjects and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of immediate-release Levetiracetam in these patients. Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [ see Clinical Pharmacology (12.3) ]. 8.6 Renal Impairment The effect of Levetiracetam Extended-release Tablets on renally impaired patients was not assessed in the controlled study. However, it is expected that the effect on Levetiracetam Extended-release Tablets-treated patients would be similar to the effect seen in controlled studies of immediate-release Levetiracetam tablets. Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance [ see Clinical Pharmacology (12.3) ]. Dose adjustment is recommended for patients with impaired renal function [ see Dosage and Administration (2.2) ]. 10 OVERDOSAGE 10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans The signs and symptoms for Levetiracetam Extended-release Tablets overdose are expected to be similar to those seen with immediate-release Levetiracetam tablets. The highest known dose of oral immediate-release Levetiracetam received in the clinical development program was 6,000 mg/day. Other than drowsiness, there were no adverse reactions in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with immediate-release Levetiracetam overdoses in postmarketing use. 10.2 Management of Overdose There is no specific antidote for overdose with Levetiracetam Extended-release Tablets. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient's clinical status. A Certified Poison Control Center should be contacted for up to date information on the management of overdose with Levetiracetam Extended-release Tablets. 10.3 Hemodialysis Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient's clinical state or in patients with significant renal impairment. 11 DESCRIPTION Roweepra XR is an antiepileptic drug available as 500 mg and 750 mg (white) extended-release tablets for oral administration. The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C 8 H 14 N 2 O 2 and its molecular weight is 170.21. Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs). It has the following structural formula: Levetiracetam is a white to off-white crystalline powder with a faint odor and a bitter taste. It is very soluble in water (104.0 g/100 mL). It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane. (Solubility limits are expressed as g/100 mL solvent.) Roweepra XR tablets contain the labeled amount of levetiracetam. Inactive ingredients: colloidal silicon dioxide, ethylcellulose, glyceryl behenate, hypromellose2910, lactose monohydrate, povidone K90, magnesium stearate, titanium dioxide and triacetin. The medication is combined with a drug release controlling polymer that provides a drug release at a controlled rate. The biologically inert components of the tablet may occasionally remain intact during GI transit and will be eliminated in the feces as a soft, hydrated mass. USP dissolution test is pending 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown. The antiepileptic activity of levetiracetam was assessed in a number of animal models of epileptic seizures. Levetiracetam did not inhibit single seizures induced by maximal stimulation with electrical current or different chemoconvulsants and showed only minimal activity in submaximal stimulation and in threshold tests. Protection was observed, however, against secondarily generalized activity from focal seizures induced by pilocarpine and kainic acid, two chemoconvulsants that induce seizures that mimic some features of human complex partial seizures with secondary generalization. Levetiracetam also displayed inhibitory properties in the kindling model in rats, another model of human complex partial seizures, both during kindling development and in the fully kindled state. The predictive value of these animal models for specific types of human epilepsy is uncertain. In vitro and in vivo recordings of epileptiform activity from the hippocampus have shown that levetiracetam inhibits burst firing without affecting normal neuronal excitability, suggesting that levetiracetam may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity. Levetiracetam at concentrations of up to 10 µM did not demonstrate binding affinity for a variety of known receptors, such as those associated with benzodiazepines, GABA (gamma-aminobutyric acid), glycine, NMDA (N-methyl-D-aspartate), re-uptake sites, and second messenger systems. Furthermore, in vitro studies have failed to find an effect of levetiracetam on neuronal voltage-gated sodium or T-type calcium currents and levetiracetam does not appear to directly facilitate GABAergic neurotransmission. However, in vitro studies have demonstrated that levetiracetam opposes the activity of negative modulators of GABA- and glycine-gated currents and partially inhibits N-type calcium currents in neuronal cells. A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam. Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis. Although the molecular significance of levetiracetam binding to synaptic vesicle protein SV2A is not understood, levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated with the potency of their antiseizure activity in audiogenic seizure-prone mice. These findings suggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug. 12.2 Pharmacodynamics Effects on QTc Interval The effects of Levetiracetam Extended-release Tablets on QTc prolongation is expected to be the same as that of immediate-release Levetiracetam. The effect of immediate-release Levetiracetam on QTc prolongation was evaluated in a randomized, double-blind, positive-controlled (moxifloxacin 400 mg) and placebo-controlled crossover study of Levetiracetam (1,000 mg or 5,000 mg) in 52 healthy subjects. The upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 milliseconds. Therefore, there was no evidence of significant QTc prolongation in this study. 12.3 Pharmacokinetics Overview Bioavailability of Levetiracetam Extended-release Tablets is similar to that of the immediate-release Levetiracetam tablets. The pharmacokinetics (AUC and C max ) were shown to be dose proportional after single dose administration of 1,000 mg, 2,000 mg, and 3,000 mg extended-release levetiracetam. Plasma half-life of extended-release levetiracetam is approximately 7 hours. Levetiracetam is almost completely absorbed after oral administration. The pharmacokinetics of levetiracetam are linear and timeinvariant, with low intra- and inter-subject variability. Levetiracetam is not significantly protein-bound (> <10% bound) and its volume of distribution is close to the volume of intracellular and extracellular water. Sixty-six percent (66%) of the dose is renally excreted unchanged. The major metabolic pathway of levetiracetam (24% of dose) is an enzymatic hydrolysis of the acetamide group. It is not liver cytochrome P450 dependent. The metabolites have no known pharmacological activity and are renally excreted. Plasma half-life of levetiracetam across studies is approximately 6-8 hours. The half-life is increased in the elderly (primarily due to impaired renal clearance) and in subjects with renal impairment. Absorption and Distribution Extended-release levetiracetam peak plasma concentrations occur in about 4 hours. The time to peak plasma concentrations is about 3 hours longer with extended-release levetiracetam than with immediate-release tablets. Single administration of two 500 mg extended-release levetiracetam tablets once daily produced comparable maximal plasma concentrations and area under the plasma concentration versus time as did the administration of one 500 mg immediate-release tablet twice daily in fasting conditions. After multiple dose extended-release levetiracetam tablets intake, extent of exposure (AUC 0-24 ) was similar to extent of exposure after multiple dose immediate-release tablets intake. C max and C min were lower by 17% and 26% after multiple dose extended-release levetiracetam tablets intake in comparison to multiple dose immediate-release tablets intake. Intake of a high fat, high calorie breakfast before the administration of extended-release levetiracetam tablets resulted in a higher peak concentration, and longer median time to peak. The median time to peak (T max ) was 2 hours longer in the fed state. Two 750 mg extended-release levetiracetam tablets were bioequivalent to a single administration of three 500 mg extended-release levetiracetam tablets. Metabolism Levetiracetam is not extensively metabolized in humans. The major metabolic pathway is the enzymatic hydrolysis of the acetamide group, which produces the carboxylic acid metabolite, ucb L057 (24% of dose) and is not dependent on any liver cytochrome P450 isoenzymes. The major metabolite is inactive in animal seizure models. Two minor metabolites were identified as the product of hydroxylation of the 2-oxo-pyrrolidine ring (2% of dose) and opening of the 2-oxo-pyrrolidine ring in position 5 (1% of dose). There is no enantiomeric interconversion of levetiracetam or its major metabolite. Elimination Levetiracetam plasma half-life in adults is 7 1 hour and is unaffected by either dose or repeated administration. Levetiracetam is eliminated from the systemic circulation by renal excretion as unchanged drug which represents 66% of administered dose. The total body clearance is 0.96 mL/min/kg and the renal clearance is 0.6 mL/min/kg. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. The metabolite ucb L057 is excreted by glomerular filtration and active tubular secretion with a renal clearance of 4 mL/min/kg. Levetiracetam elimination is correlated to creatinine clearance. Levetiracetam clearance is reduced in patients with impaired renal function [s ee Dosage and Administration (2.2) and Use in Specific Populations (8.6) ]. Specific Populations Elderly There are insufficient pharmacokinetic data to specifically address the use of extended-release levetiracetam in the elderly population. Pharmacokinetics of immediate-release levetiracetam were evaluated in 16 elderly subjects (age 61-88 years) with creatinine clearance ranging from 30 to 74 mL/min. Following oral administration of twice-daily dosing for 10 days, total body clearance decreased by 38% and the half-life was 2.5 hours longer in the elderly compared to healthy adults. This is most likely due to the decrease in renal function in these subjects. Pediatric Patients An open label, multicenter, parallel-group, two-arm study was conducted to evaluate the pharmacokinetics of Levetiracetam Extended-release Tablets in pediatric patients (13 to 16 years old) and in adults (18 to 55 years old) with epilepsy. Levetiracetam Extended-release Tablets oral tablets (1,000 mg to 3,000 mg) were administered once daily with a minimum of 4 days and a maximum of 7 days of treatment to 12 pediatric patients and 13 adults in the study. Dose-normalized steady-state exposure parameters, C max and AUC, were comparable between pediatric and adult patients. Pregnancy Roweepra XR levels may decrease during pregnancy. Gender Extended-release levetiracetam C max was 21-30% higher and AUC was 8-18% higher in women (N=12) compared to men (N=12). However, clearances adjusted for body weight were comparable. Race Formal pharmacokinetic studies of the effects of race have not been conducted with extended-release or immediate-release levetiracetam. Cross study comparisons involving Caucasians (N=12) and Asians (N=12), however, show that pharmacokinetics of immediate-release levetiracetam were comparable between the two races. Because levetiracetam is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected. Renal Impairment The effect of Levetiracetam Extended-release Tablets on renally impaired patients was not assessed in the controlled study. However, it is expected that the effect on Levetiracetam Extended-release Tablets-treated patients would be similar to that seen in controlled studies of immediate-release Levetiracetam. In patients with end stage renal disease on dialysis, it is recommended that immediate-release Levetiracetam tablets be used instead of Levetiracetam Extended-release Tablets. The disposition of immediate-release levetiracetam was studied in adult subjects with varying degrees of renal function. Total body clearance of levetiracetam is reduced in patients with impaired renal function by 40% in the mild group (CLcr = 50-80 mL/min), 50% in the moderate group (CLcr = 30-50 mL/min) and 60% in the severe renal impairment group (CLcr> <30 mL/min). Clearance of levetiracetam is correlated with creatinine clearance. In anuric (end stage renal disease) patients, the total body clearance decreased 70% compared to normal subjects (CLcr> 80mL/min). Approximately 50% of the pool of levetiracetam in the body is removed during a standard 4 hour hemodialysis procedure. [ see Dosage and Administration (2.2) ]. Hepatic Impairment In subjects with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment, the pharmacokinetics of levetiracetam were unchanged. In patients with severe hepatic impairment (Child-Pugh C), total body clearance was 50% that of normal subjects, but decreased renal clearance accounted for most of the decrease. No dose adjustment is needed for patients with hepatic impairment. Drug Interactions In vitro data on metabolic interactions indicate that levetiracetam is unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above C max levels achieved within the therapeutic dose range, are neither inhibitors of, nor high affinity substrates for, human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid. Potential pharmacokinetic interactions of or with levetiracetam were assessed in clinical pharmacokinetic studies (phenytoin, valproate, warfarin, digoxin, oral contraceptive, probenecid) and through pharmacokinetic screening with immediate-release Levetiracetam tablets in the placebo-controlled clinical studies in epilepsy patients. The potential for drug interactions for Levetiracetam Extended-release Tablets is expected to be essentially the same as that with immediate-release Levetiracetam tablets. Phenytoin Immediate-release Levetiracetam tablets (3,000 mg daily) had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. Pharmacokinetics of levetiracetam were also not affected by phenytoin. Valproate Immediate-release Levetiracetam tablets (1,500 mg twice daily) did not alter the pharmacokinetics of valproate in healthy volunteers. Valproate 500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion. There also was no effect on exposure to and the excretion of the primary metabolite, ucb L057. Other Antiepileptic Drugs Potential drug interactions between immediate-release Levetiracetam tablets and other AEDs (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone and valproate) were also assessed by evaluating the serum concentrations of levetiracetam and these AEDs during placebo-controlled clinical studies. These data indicate that levetiracetam does not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of levetiracetam. Oral Contraceptives Immediate-release Levetiracetam tablets (500 mg twice daily) did not influence the pharmacokinetics of an oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel, or of the luteinizing hormone and progesterone levels, indicating that impairment of contraceptive efficacy is unlikely. Coadministration of this oral contraceptive did not influence the pharmacokinetics of levetiracetam. Digoxin Immediate-release Levetiracetam tablets (1,000 mg twice daily) did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every d shopper
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