Elepsia XR

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.

Pharmacodynamics

The effects of levetiracetam extended-release tablets on QTc prolongation is expected to be the same as that of immediate-release levetiracetam tablets. The effect of immediate-release levetiracetam tablets on QTc prolongation was evaluated in a randomized, double-blind, positive-controlled (moxifloxacin 400 mg) and placebo-controlled crossover study of immediate-release levetiracetam tablets (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.

Pharmacokinetics

Bioavailability of levetiracetam extended-release tablets is similar to that of the immediate-release levetiracetam tablets. The pharmacokinetics (AUC and Cmax) 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. ELEPSIA XR 1,500 mg tablets are bioequivalent to Keppra XR (levetiracetam) extended release tablets (2 tablets of 750 mg) in both fasted and fed states.

Levetiracetam is almost completely absorbed after oral administration. The pharmacokinetics of levetiracetam are linear and time-invariant, 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 to 8 hours. The half-life is increased in the elderly (primarily due to impaired renal clearance) and in subjects with renal impairment.

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. After multiple dose levetiracetam extended-release tablets intake, extent of exposure (AUC0-24) was similar to extent of exposure after multiple dose immediate-release tablets intake. Cmax and Cmin were lower by 17% and 26% after multiple dose levetiracetam extended-release tablets intake in comparison to multiple dose immediate-release tablets intake. Intake of a high fat, high calorie breakfast before the administration of levetiracetam extended-release tablets resulted in a longer median time to peak. The median time to peak (Tmax) was 3 to 4.5 hours longer in the fed state. There was no effect on peak plasma concentration however; the extent of exposure (AUC) was 21 to 25% higher.

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.

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 [see Use in Specific Populations and DOSAGE AND ADMINISTRATION].

Special Populations

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 to 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.

An open label, multicenter, parallel-group, two-arm study was conducted to evaluate the pharmacokinetics of extended-release levetiracetam in pediatric patients (13 to 16 years old) and in adults (18 to 55 years old) with epilepsy. Levetiracetam extended-release 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, Cmax and AUC, were comparable between pediatric and adult patients.

Levetiracetam extended-release tablets levels may decrease during pregnancy.

When given in a single dose, extended-release levetiracetam Cmax was 21 to 30% higher and AUC was 8 to 18% higher in women (N=12) compared to men (N=12). However, clearances adjusted for body weight were comparable. Similar results were observed in a multiple dose study.

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.

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 ELEPSIA XR-treated patients would be similar to that seen in controlled studies of immediate-release levetiracetam 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 to 80 mL/min), 50% in the moderate group (CLcr = 30 to 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 > 80 mL/min). Approximately 50% of the pool of levetiracetam in the body is removed during a standard 4-hour hemodialysis procedure.

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.

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 Cmax 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.

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.

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.

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.

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.

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 day. Coadministration of digoxin did not influence the pharmacokinetics of levetiracetam.

Immediate-release levetiracetam tablets (1,000 mg twice daily) did not influence the pharmacokinetics of R and S warfarin. Prothrombin time was not affected by levetiracetam. Coadministration of warfarin did not affect the pharmacokinetics of levetiracetam.

Probenecid, a renal tubular secretion blocking agent, administered at a dose of 500 mg four times a day, did not change the pharmacokinetics of levetiracetam 1,000 mg twice daily. Css max of the metabolite, ucb L057, was approximately doubled in the presence of probenecid while the fraction of drug excreted unchanged in the urine remained the same. Renal clearance of ucb L057 in the presence of probenecid decreased 60%, probably related to competitive inhibition of tubular secretion of ucb L057. The effect of immediate-release levetiracetam tablets on probenecid was not studied.

Clinical Studies

The effectiveness of levetiracetam extended-release tablets as adjunctive therapy in partial onset seizures in adults was established in one multicenter, randomized, double-blind, placebo-controlled clinical study in patients who had refractory partial onset seizures with or without secondary generalization. This was supported by the demonstration of efficacy of immediate-release levetiracetam tablets (see below) in partial seizures in three multicenter, randomized, double-blind, placebo-controlled clinical studies in adults, as well as a demonstration of comparable bioavailability between the extended-release and immediate-release formulations [see CLINICAL PHARMACOLOGY] in adults. The effectiveness for levetiracetam extended-release tablets as adjunctive therapy in partial onset seizures in pediatric patients, 12 years of age and older, was based upon a single pharmacokinetic study showing comparable pharmacokinetics of levetiracetam extended-release tablets in adults and adolescents [see CLINICAL PHARMACOLOGY]. All studies are described below.

Levetiracetam Extended-Release Tablets In Adults

The effectiveness of levetiracetam extended-release tablets as adjunctive therapy (added to other antiepileptic drugs) was established in one multicenter, randomized, double-blind, placebo-controlled clinical study across 7 countries in patients who had refractory partial onset seizures with or without secondary generalization (Study 1).

Patients enrolled in Study 1 had at least eight partial seizures with or without secondary generalization during the 8-week baseline period and at least two partial seizures in each 4-week interval of the baseline period. Patients were taking a stable dose regimen of at least one AED, and could take a maximum of three AEDs. After a prospective baseline period of 8 weeks, 158 patients were randomized to placebo (N=79) or 1,000 mg (two 500 mg tablets) of levetiracetam extended-release tablets (N=79), given once daily over a 12-week treatment period.

The primary efficacy endpoint in Study 1 was the percent reduction over placebo in mean weekly frequency of partial onset seizures. The median percent reduction in weekly partial onset seizure frequency from baseline over the treatment period was 46% in the levetiracetam extended-release tablets 1,000 mg treatment group (N=74) and 33% in the placebo group (N=78). The estimated percent reduction over placebo in weekly partial onset seizure frequency over the treatment period was 14% (statistically significant).

The relationship between the effectiveness of the same daily dose of levetiracetam extended-release tablets and immediate-release levetiracetam tablets has not been studied and is unknown.

Immediate-release Levetiracetam Tablets In Adults

The effectiveness of immediate-release levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in adults was established in three multicenter, randomized, double-blind, placebo-controlled clinical studies in patients who had refractory partial onset seizures with or without secondary generalization (Studies 2, 3, and 4). The tablet formulation was used in all three studies. In these studies, 904 patients were randomized to placebo, levetiracetam 1,000 mg, levetiracetam 2,000 mg, or levetiracetam 3,000 mg/day. Patients enrolled in Study 2 or Study 3 had refractory partial onset seizures for at least two years, and had taken two or more AEDs. Patients enrolled in Study 4 had refractory partial onset seizures for at least 1 year and had taken one AED. At the time of the study, patients were taking a stable dose regimen of at least one AED, and could take a maximum of two AEDs. During the baseline period, patients had to have experienced at least two partial onset seizures during each 4-week period.

Study 2 was a double-blind, placebo-controlled, parallel-group study conducted at 41 sites in the United States, comparing immediate-release levetiracetam 1,000 mg/day (N=97), immediate-release levetiracetam 3,000 mg/day (N=101), and placebo (N=95), given in equally divided doses twice daily. After a prospective baseline period of 12 weeks, patients in Study 2 were randomized to one of the three treatment groups described above. The 18-week treatment period consisted of a 6-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant. The primary measure of effectiveness in Study 2 was a between-group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥ 50% reduction from baseline in partial onset seizure frequency). The results of Study 2 are displayed in Table 6.

Table 6: Reduction In Mean Over Placebo In Weekly Frequency Of Partial Onset Seizures In Study 2

The percentage of patients (y-axis) who achieved ≥ 50% reduction from baseline in weekly partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatment groups (x-axis) in Study 2 is presented in Figure 1.

Figure 1 :Responder Rate ( ≥ 50% Reduction From Baseline) In Study 2

* statistically significant versus placebo

Study 3 was a double-blind, placebo-controlled, crossover study conducted at 62 centers in Europe, comparing immediate-release levetiracetam 1,000 mg/day (N=106), immediate-release levetiracetam 2,000 mg/day (N=105), and placebo (N=111), given in equally divided doses twice daily.

The first period of the study (Period A) was designed to be analyzed as a parallel-group study. After a prospective baseline period of up to 12 weeks, patients in Study 3 were randomized to one of the three treatment groups described above. The 16-week treatment period consisted of the 4-week titration period followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant. The primary measure of effectiveness in Study 3 was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥ 50% reduction from baseline in partial onset seizure frequency). The results of the analysis of Period A are displayed in Table 7.

Table 7: Reduction In Mean Over Placebo In Weekly Frequency Of Partial Onset Seizures In Study 3: Period A

The percentage of patients (y-axis) who achieved ≥ 50% reduction from baseline in weekly partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatment groups (x-axis) in Study 3 is presented in Figure 2.

Figure 2 :Responder Rate ( ≥ 50% Reduction From Baseline) In Study 3 : Period A

* statistically significant versus placebo

The comparison of immediate-release levetiracetam 2,000 mg/day to immediate-release levetiracetam 1,000 mg/day for responder rate in Study 3 was statistically significant (P=0.02). Analysis of the trial as a cross-over study yielded similar results.

Study 4 was a double-blind, placebo-controlled, parallel-group study conducted at 47 centers in Europe comparing immediate-release levetiracetam 3,000 mg/day (N=180) and placebo (N=104) in patients with refractory partial onset seizures, with or without secondary generalization, receiving only one concomitant AED. Study drug was given in two divided doses. After a prospective baseline period of 12 weeks, patients in Study 4 were randomized to one of two treatment groups described above. The 16-week treatment period consisted of a 4-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED doses were held constant. The primary measure of effectiveness in Study 4 was a between group comparison of the percent reduction in weekly seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥ 50% reduction from baseline in partial onset seizure frequency).

Table 8 displays the results of Study 4.

Table 8: Reduction In Mean Over Placebo In Weekly Frequency Of Partial Onset Seizures In Study 4

The percentage of patients (y-axis) who achieved ≥ 50% reduction from baseline in weekly partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) in Study 4 is presented in Figure 3.

Figure 3: Responder Rate ( ≥ 50% Reduction From Baseline) In Study 4

* statistically significant versus placebo

Immediate-release Levetiracetam In Pediatric Patients 4 Years To 16 Years

The use of levetiracetam extended-release tablets in pediatric patients 12 years of age and older is supported by Study 5, which was conducted using immediate-release levetiracetam. Levetiracetam extended-release tablets are not indicated in children below 12 years of age.

The effectiveness of immediate-release levetiracetam as adjunctive therapy in pediatric patients was established in a multicenter, randomized double-blind, placebo-controlled study, conducted at 60 sites in North America, in children 4 to 16 years of age with partial seizures uncontrolled by standard antiepileptic drugs (Study 5). Eligible patients on a stable dose of 1 to 2 AEDs, who still experienced at least 4 partial onset seizures during the 4 weeks prior to screening, as well as at least 4 partial onset seizures in each of the two 4-week baseline periods, were randomized to receive either immediate-release levetiracetam or placebo. The enrolled population included 198 patients (levetiracetam N=101; placebo N=97) with refractory partial onset seizures, with or without secondarily generalization. Study 5 consisted of an 8-week baseline period and 4-week titration period followed by a 10-week evaluation period. Dosing was initiated at a dose of 20 mg/kg/day in two divided doses. During the treatment period, the immediate-release levetiracetam doses were adjusted in 20 mg/kg/day increments, at 2-week intervals to the target dose of 60 mg/kg/day. The primary measure of effectiveness in Study 5 was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire 14-week randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥ 50% reduction from baseline in partial onset seizure frequency per week). Table 9 displays the results of this study.

Table 9: Reduction In Mean Over Placebo In Weekly Frequency Of Partial Onset Seizures in Study 5

The percentage of patients (y-axis) who achieved ≥ 50% reduction in weekly partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (xaxis) in Study 5 is presented in Figure 4.

Figure 4 :Responder Rate ( ≥ 50% Reduction From Baseline) In Study 5

*statistically significant versus placebo

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Elepsia XR there are no specific foods that you must exclude from your diet when receiving Elepsia XR.

Take Elepsia XR exactly as prescribed by your doctor. Follow the directions on your prescription label carefully. Your doctor will determine the best dose for you. 

The recommended starting dose of Elepsia XR tablets, for the treatment of partial onset seizures in patients ≥ 12 years of age with epilepsy, is 1000 mg once daily. The dosage may be adjusted in increments of 1000 mg every 2 weeks, to a maximum recommended dose of 3000 mg once daily.

Your doctor may change your dose changes based on how your kidney works. 

The following serious adverse reactions are discussed below and elsewhere in the labeling:

• Psychiatric Reactions [see WARNINGS AND PRECAUTIONS]
• Suicidal Behavior And Ideation [see WARNINGS AND PRECAUTIONS]
• Somnolence And Fatigue [see WARNINGS AND PRECAUTIONS]
• Serious Dermatological Reactions [see WARNINGS AND PRECAUTIONS]
• Coordination Difficulties [see WARNINGS AND PRECAUTIONS]
• Withdrawal Seizures [see WARNINGS AND PRECAUTIONS]
• Hematologic Abnormalities [see WARNINGS AND PRECAUTIONS]

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.

The prescriber should be aware that the adverse reaction incidence figures in the following table, obtained when levetiracetam extended-release tablets were added to concurrent AED therapy, cannot be used to predict the frequency of adverse reactions in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical trials. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the adverse reaction incidences in the population studied.

In the controlled clinical study using levetiracetam extended-release tablets in patients with partial onset seizures (Study 1), the most frequently reported 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 treated with levetiracetam extended-release tablets participating in the placebo-controlled study (Study 1) 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: Incidence (%) Of Adverse Reactions In The Placebo-Controlled, Add-On Study By Body System (Adverse Reactions Occurred In At Least 5% Of Levetiracetam Extended-Release Tablets-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients)

In the controlled clinical study using levetiracetam extended-release tablets, 5.2% of patients receiving levetiracetam extended-release tablets and 2.5% 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.

Table 4 lists the adverse reactions seen 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 frequently reported 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 treated with immediate-release levetiracetam tablets participating 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: Incidence (%) Of Adverse Reactions In Placebo-Controlled, Add-On Studies In Adults Experiencing Partial Onset Seizures By Body System (Adverse Reactions Occurred In At Least 1% Of Immediate-Release Levetiracetam Tablets-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients)

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 tablets 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 tablets and were more common than in pediatric patients on placebo. In these studies, either immediate-release levetiracetam tablets or placebo was added to concurrent AED therapy.

Table 5: Incidence (%) Of Adverse Reactions In Pooled Placebo-Controlled, Add-On Studies In Pediatric Patients Ages 4 to 16 Years Experiencing Partial Onset Seizures By Body System (Adverse Reactions Occurred In At Least 2% Of Patients Treated With Immediate-Release Levetiracetam Tablets And Occurred More Frequently Than Patients on Placebo)

In controlled pediatric clinical studies in patients 4 to 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 well-controlled studies of immediate-release levetiracetam tablets: balance disorder, disturbance in attention, eczema, hyperkinesia, memory impairment, myalgia, personality disorders, pruritus, and vision blurred.

There are insufficient data for levetiracetam extended-release tablets to support a statement regarding the distribution of adverse experience reports by gender, age and race.

Read the entire FDA prescribing information for Elepsia XR (Levetiracetam Extended-release Tablets)

Dosage Information

Elepsia XR is administered once daily.

Treatment should be initiated with a dose of 1,000 mg once daily. The once daily dosage may be adjusted in increments of 1,000 mg every 2 weeks to a maximum recommended once daily dose of 3,000 mg.

Elepsia XR should be taken whole; do not split or cut tablets.

Dosage in Patients with Renal Impairment

Elepsia XR is not recommended for patients with moderate or severe renal impairment.  Recommended doses and adjustment for patients with mild renal impairment are shown in Table 1. In order to calculate the dose recommended for patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated. To do this, an estimate of the patient’s creatinine clearance (CLcr) in mL/min must first be calculated using the following formula:

Then CLcr is adjusted for body surface area (BSA) as follows:

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 tablets 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 tablets overdoses in postmarketing use.

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.

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.

Elepsia XR contains levetiracetam, an antiepileptic drug, as 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 C8H14N2O2 and its molecular weight is 170.21. Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs). It has the following structural formula:

Levetiracetam, USP is a white to off-white crystalline powder with a faint odor and a bitter taste. It is very soluble in water (104 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.

Each extended-release tablet contains 1,000 mg or 1,500 mg of levetiracetam. Inactive ingredients: povidone, hypromellose, amino methacrylate copolymer, colloidal silicon dioxide, magnesium stearate, talc, silicified microcrystalline cellulose, crospovidone, sodium lauryl sulfate, FD&C Blue #1 aluminum lake, ethylcellulose, dibutyl sebacate, triethyl citrate, polysorbate 20, polyvinyl alcohol, polyethylene glycol, and polysorbate 80. The imprinting ink contains shellac glaze, iron oxide black, N-butyl alcohol, propylene glycol, and ammonium hydroxide.

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.

Pharmacodynamics

Effects on QTc Interval

The effects of levetiracetam extended-release tabletson QTc prolongation is expected to be the same as that of immediate-release levetiracetam tablets. The effect of immediate-release levetiracetam tabletson QTc prolongation was evaluated in a randomized, double-blind, positive-controlled (moxifloxacin 400 mg) and placebo-controlled crossover study of immediate-release levetiracetam tablets (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.

Pharmacokinetics

Overview

Bioavailability of levetiracetam extended-release tablets is similar to that of the immediate-release levetiracetam tablets.The pharmacokinetics (AUC and Cmax) 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. Elepsia XR 1,500 mg tablets are bioequivalent to Keppra XR (levetiracetam) extended release tablets (2 tablets of 750 mg) in both fasted and fed states.

Levetiracetam is almost completely absorbed after oral administration. The pharmacokinetics of levetiracetam are linear and time-invariant, 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 to 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. After multiple dose levetiracetam extended-release tablets intake, extent of exposure (AUC0-24) was similar to extent of exposure after multiple dose immediate-release tablets intake. Cmax and Cmin were lower by 17% and 26% after multiple dose levetiracetam extended-release tablets intake in comparison to multiple dose immediate-release tablets intake. Intake of a high fat, high calorie breakfast before the administration of levetiracetam extended-release tablets resulted in a longer median time to peak. The median time to peak (Tmax) was 3 to 4.5 hours longer in the fed state. There was no effect on peak plasma concentration however; the extent of exposure (AUC) was 21 to 25% higher.

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 [see Use in Specific Populations (8.6)and Dosage and Administration (2.1)].

Special 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 to 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 extended-release levetiracetam in pediatric patients (13 to 16 years old) and in adults (18 to 55 years old) with epilepsy. Levetiracetam extended-release 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, Cmax and AUC, were comparable between pediatric and adult patients.

Pregnancy

Levetiracetam extended-release tablets levels may decrease during pregnancy.

Gender

When given in a single dose, extended-release levetiracetam Cmax was 21 to 30% higher and AUC was 8 to 18% higher in women (N=12) compared to men (N=12). However, clearances adjusted for body weight were comparable. Similar results were observed in a multiple dose study.  

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 Elepsia XR-treated patients would be similar to that seen in controlled studies of immediate-release levetiracetam 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 to 80 mL/min), 50% in the moderate group (CLcr = 30 to 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 >80 mL/min). Approximately 50% of the pool of levetiracetam in the body is removed during a standard 4- hour hemodialysis procedure.

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.

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 Cmax 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 day. Coadministration of digoxin did not influence the pharmacokinetics of levetiracetam.

Warfarin

Immediate-release levetiracetam tablets (1,000 mg twice daily) did not influence the pharmacokinetics of R and S warfarin. Prothrombin time was not affected by levetiracetam. Coadministration of warfarin did not affect the pharmacokinetics of levetiracetam.

Probenecid

Probenecid, a renal tubular secretion blocking agent, administered at a dose of 500 mg four times a day, did not change the pharmacokinetics of levetiracetam 1,000 mg twice daily. Cssmax of the metabolite, ucb L057, was approximately doubled in the presence of probenecid while the fraction of drug excreted unchanged in the urine remained the same. Renal clearance of ucb L057 in the presence of probenecid decreased 60%, probably related to competitive inhibition of tubular secretion of ucb L057. The effect of immediate-release levetiracetam tablets on probenecid was not studied.

NDC 47133-574-83
Elepsia™ XR (levetiracetam) Extended-release Tablets
1,000 mg
Once Daily Dosing
Swallow tablets whole, do NOT chew, break, split, or crush tablets.
Rx only
30 Tablets
PHARMACIST: Please dispense with Medication Guide provided separately to each patient.

Applies to levetiracetam: oral solution, oral tablet, oral tablet for suspension, oral tablet extended release

Other dosage forms:

• intravenous solution

Along with its needed effects, levetiracetam (the active ingredient contained in Elepsia XR) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking levetiracetam:

• Aggressive or angry
• anxiety
• change in personality
• chills
• cough or hoarseness
• crying
• depersonalization
• diarrhea
• dry mouth
• euphoria
• fever
• general feeling of discomfort or illness
• headache
• hyperventilation
• irregular heartbeats
• irritability
• joint pain
• loss of appetite
• lower back or side pain
• mental depression
• muscle aches and pains
• nausea
• painful or difficult urination
• paranoia
• quick to react or overreact emotionally
• rapidly changing moods
• restlessness
• shaking
• shivering
• shortness of breath
• sleepiness or unusual drowsiness
• sore throat
• stuffy or runny nose
• sweating
• trouble sleeping
• unusual tiredness or weakness
• vomiting

• Bloody nose
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• clumsiness or unsteadiness
• discouragement
• dizziness or lightheadedness
• double vision
• earache
• feeling of constant movement of self or surroundings
• feeling sad or empty
• increase in body movements
• loss of bladder control
• loss of memory
• mood or mental changes
• outburst of anger
• pain or tenderness around the eyes and cheekbones
• problems with memory
• redness or swelling in the ear
• seizures
• sensation of spinning
• shakiness and unsteady walk
• shakiness in the legs, arms, hands, or feet
• tightness of the chest
• tiredness
• trembling or shaking of the hands or feet
• trouble concentrating
• unsteadiness, trembling, or other problems with muscle control or coordination

• Attempts at killing oneself
• being forgetful
• bleeding gums
• blistering, peeling, or loosening of the skin
• bloating
• blood in the urine or stools
• bloody, black, or tarry stools
• blurred vision
• changes in vision
• chest pain
• constipation
• dark urine
• difficulty with moving
• fast heartbeat
• fever with or without chills
• general feeling of tiredness or weakness
• high fever
• increase in body movements
• indigestion
• itching
• light-colored stools
• muscle pains or stiffness
• painful or difficult urination
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pale skin
• pinpoint red spots on the skin
• red skin lesions, often with a purple center
• red, irritated eyes
• sores, ulcers, or white spots on the lips or in the mouth
• stomach pain, continuing
• swollen glands
• swollen joints
• thoughts or attempts at killing oneself
• trouble with balance
• twitching, twisting, or uncontrolled repetitive movements of the tongue, lips, face, arms, or legs
• uncontrolled jerking or twisting movements of the hands, arms, or legs
• uncontrolled movements of the lips, tongue, or cheeks
• unexplained bleeding or bruising
• unusual bleeding or bruising
• upper right abdominal or stomach pain
• weight loss
• yellow eyes or skin

Some side effects of levetiracetam may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Loss of strength or energy
• muscle pain or weakness
• pain
• tender, swollen glands in the neck
• trouble swallowing
• unusual weak feeling
• voice changes

• Body aches or pain
• burning, dry, or itching eyes
• change in the color of the skin
• congestion
• cough increased
• rash
• sneezing

• Hair loss or thinning of the hair
• skin rash, encrusted, scaly, and oozing