Lepixa 500/Lepixa 1000/Lepixa

Levetiracetam.

Lepixa 500: Each Film-coated Tablet contains: Levetiracetam 500 mg or 1g.
Lepixa 1000: Each Film-coated Tablet contains: Levetiracetam 1g.
Lepixa: Oral solution: White to off-white crystalline with a faint odor and a bitter taste.
Each mL contains 100 mg.
Levetiracetam is an antiepileptic drug available as grape-flavored liquid (100 mg/mL) for oral administration.
Levetiracetam Oral Solution contains the labeled amount of levetiracetam.
Solution for injection: Levetiracetam injection is an antiepileptic drug available as a clear, colorless, sterile solution (100 mg/mL) for intravenous administration.
The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-(-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).
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.)
Levetiracetam injection contains 100 mg of levetiracetam per mL. It is supplied in single-use 5 mL vials containing 500 mg levetiracetam, water for injection, 45 mg sodium chloride, and buffered at approximately pH 5.5 with glacial acetic acid and 8.2 mg sodium trihydrate. Levetiracetam injection must be diluted prior to intravenous infusion [see Preparation and Administration under Dosage & Administration].
Excipients/Inactive ingredients: Lepixa: Oral solution: Sodium citrate, citric acid monohydrate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, ammonium glycyrrhizate, glycerol, maltitol liquid, acesulfame potassium, ART grape flavour, purified water.

Pharmacology: Mechanism of Action: Lepixa: 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 hyper synchronization 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.
Solution for injection: 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: Lepixa: Solution for injection: Effects on QTc Interval: The effect of Levetiracetam on QTc prolongation was evaluated in a randomized, double-blind, positive-controlled (moxifloxacin 400 mg) and placebo-controlled crossover study of Levetiracetam (1000 mg or 5000 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.
Clinical Studies: All clinical studies supporting the efficacy of Levetiracetam utilized oral formulations. The finding of efficacy of Levetiracetam injection is based on the results of studies using an oral formulation of Levetiracetam, and on the demonstration of comparable bioavailability of the oral and parenteral formulations (see Pharmacokinetics as follows).
Partial Onset Seizures: Effectiveness in Partial Onset Seizures in Adults with Epilepsy: The effectiveness of 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. The tablet formulation was used in all these studies. In these studies, 904 patients were randomized to placebo, 1000 mg, 2000 mg, or 3000 mg/day. Patients enrolled in Study 1 or Study 2 had refractory partial onset seizures for at least two years and had taken two or more classical AEDs. Patients enrolled in Study 3 had refractory partial onset seizures for at least 1 year and had taken one classical AED. At the time of the study, patients were taking a stable dose regimen of at least one 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 1: Study 1 was a double-blind, placebo-controlled, parallel-group study conducted at 41 sites in the United States comparing Levetiracetam 1000 mg/day (N=97), Levetiracetam 3000 mg/day (N=101), and placebo (N=95) given in equally divided doses twice daily. After a prospective baseline period of 12 weeks, patients were randomized to one of the three treatment groups described previously. 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 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 Study 1 are displayed in Table 1. (See Table 1.)

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

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Study 2: Study 2 was a double-blind, placebo-controlled, crossover study conducted at 62 centers in Europe comparing Levetiracetam 1000 mg/day (N=106), Levetiracetam 2000 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 were randomized to one of the three treatment groups described previously. 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 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 2. (See Table 2.)

Click on icon to see table/diagram/image

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

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The comparison of Levetiracetam 2000 mg/day to Levetiracetam 1000 mg/day for responder rate was statistically significant (P=0.02). Analysis of the trial as a cross-over yielded similar results.
Study 3: Study 3 was a double-blind, placebo-controlled, parallel-group study conducted at 47 centers in Europe comparing Levetiracetam 3000 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 were randomized to one of two treatment groups described previously. 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 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 3 displays the results of the analysis of Study 3. (See Table 3.)

Click on icon to see table/diagram/image

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

Click on icon to see table/diagram/image

Effectiveness in Partial Onset Seizures in Pediatric Patients 4 Years to 16 Years with Epilepsy: Study 4 was a multicenter, randomized double-blind, placebo-controlled study, in pediatric patients 4 to 16 years of age with partial seizures uncontrolled by standard antiepileptic drugs (AEDs). Study 4 was conducted at 60 sites in North America. The study consisted of an 8-week baseline period and 4-week titration period followed by a 10-week evaluation period. Eligible patients who still experienced, on a stable dose of 1-2 AEDs, 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 Levetiracetam or placebo. Dosing was initiated at a dose of 20 mg/kg/day in two divided doses. During the treatment period, 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 efficacy 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). The enrolled population included 198 patients (Levetiracetam N=101, placebo N=97) with refractory partial onset seizures, whether or not secondarily generalized. Table 4 displays the results of Study 4. (See Table 4.)

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

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Effectiveness in Partial Onset Seizures in Pediatric Patients 1 Month to <4 Years with Epilepsy: Study 5 was a multicenter, randomized double-blind, placebo-controlled study, in pediatric patients 1 month to less than 4 years of age with partial seizures, uncontrolled by standard epileptic drugs (AEDs). Study 5 was conducted at 62 sites in North America, South America, and Europe. Study 5 consisted of a 5-day evaluation period, which included a 1-day titration period followed by a 4-day maintenance period. Eligible patients who experienced, on a stable dose of 1-2 AEDs, at least 2 partial onset seizures during the 48-hour baseline video EEG were randomized to receive either Levetiracetam or placebo. Randomization was stratified by age range as follows: 1 month to less than 6 months of age (N=4 treated with Levetiracetam), 6 months to less than 1 year of age (N=8 treated with Levetiracetam), 1 year to less than 2 years of age (N=20 treated with Levetiracetam), and 2 years to less than 4 years of age (N=28 treated with Levetiracetam). Levetiracetam dosing was determined by age and weight as follows: children 1 month to less than 6 months old were randomized to a target dose of 40 mg/kg/day, and children 6 months to less than 4 years old were randomized to a target dose of 50 mg/kg/day. The primary measure of efficacy was the responder rate (percent of patients with ≥50% reduction from baseline in average daily partial onset seizure frequency) assessed by a blinded central reader using a 48-hour video EEG performed during the last two days of the 4-day maintenance period. The enrolled population included 116 patients (Levetiracetam N=60, placebo N=56) with refractory partial onset seizures, whether or not secondarily generalized. A total of 109 patients were included in the efficacy analysis. A statistically significant difference between Levetiracetam and placebo was observed in Study 5 (see Figure 5). The treatment effect associated with Levetiracetam was consistent across age groups. (See Figure 5.)

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Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy: Study 6 was a multicenter, randomized, double-blind, placebo-controlled study in patients 12 years of age and older with juvenile myoclonic epilepsy (JME) experiencing myoclonic seizures. Study 6 was conducted at 37 sites in 14 countries. Eligible patients on a stable dose of 1 antiepileptic drug (AED) experiencing one or more myoclonic seizures per day for at least 8 days during the prospective 8-week baseline period were randomized to either Levetiracetam or placebo (Levetiracetam N=60, placebo N=60). Patients were titrated over 4 weeks to a target dose of 3000 mg/day and treated at a stable dose of 3000 mg/day over 12 weeks (evaluation period). Study drug was given in 2 divided doses. The primary measure of efficacy was the proportion of patients with at least 50% reduction in the number of days per week with one or more myoclonic seizures during the treatment period (titration + evaluation periods) as compared to baseline. Table 5 displays the results for the 113 patients with JME in this study. Of 120 patients enrolled, 113 had a diagnosis of confirmed or suspected JME. The results of Study 6 are displayed in Table 5. (See Table 5.)

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Primary Generalized Tonic-Clonic Seizures: Effectiveness in Primary Generalized Tonic-Clonic Seizures in Patients ≥6 years of age: Study 7 was a multicenter, randomized, double-blind, placebo-controlled study in patients 6 years of age and older with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic (PGTC) seizures. Study 7 was conducted at 50 sites in 8 countries. Eligible patients on a stable dose of 1 or 2 antiepileptic drugs (AEDs) experiencing at least 3 PGTC seizures during the 8-week combined baseline period (at least one PGTC seizure during the 4 weeks prior to the prospective baseline period and at least one PGTC seizure during the 4-week prospective baseline period) were randomized to either Levetiracetam or placebo. The 8-week combined baseline period is referred to as "baseline" in the remainder of this section. Patients were titrated over 4 weeks to a target dose of 3000 mg/day for adults or a pediatric target dose of 60 mg/kg/day and treated at a stable dose of 3000 mg/day (or 60 mg/kg/day for children) over 20 weeks (evaluation period). Study drug was given in 2 equally divided doses per day. The primary measure of efficacy was the percent reduction from baseline in weekly PGTC seizure frequency for Levetiracetam and placebo treatment groups over the treatment period (titration + evaluation periods). The population included 164 patients (Levetiracetam N=80, placebo N=84) with idiopathic generalized epilepsy (predominantly juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy, or epilepsy with Grand Mal seizures on awakening) experiencing primary generalized tonic-clonic seizures. Each of these syndromes of idiopathic generalized epilepsy was well represented in this patient population. There was a statistically significant decrease from baseline in PGTC frequency in the Levetiracetam-treated patients compared to the placebo-treated patients in Study 7 (see Table 6).

Click on icon to see table/diagram/image

The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in PGTC seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 6. (See Figure 6.)

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Pharmacokinetics: Lepixa 500/Lepixa 1000: Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear and time-dependent with low intra and inter-subject variability. There is no modification of the clearance after repeated administration. There is no evidence for any relevant gender, race or circadian variability. Due to its complete and linear absorption, plasma levels can be predicted from the oral dose of Levetiracetam expressed as mg/kg body weight. Therefore, there is no need for plasma level monitoring of Levetiracetam. A significant correlation between saliva and plasma concentrations has been shown in adults and children.
Adults and Adolescents: Absorption: Levetiracetam is rapidly absorbed after oral administration. Oral absolute bioavailability is close to 100%. Peak plasma concentrations (C_max) are achieved at 1.3 hrs after dosing. Steady-state is achieved after 2 days of a twice-daily administration schedule. Peak concentrations (C_max) are typically 31 and 43 mcg/mL following a single 1000-mg dose and repeated 1000 mg twice daily dose, respectively. The extent of absorption is dose-dependent and is not altered by food.
Distribution: No tissue distribution data are available in humans. Neither Levetiracetam nor its primary metabolite are significantly bound to plasma proteins (<10%). The volume of distribution of Levetiracetam is approximately 0.5-0.7 L/kg, a value close to the total body water volume.
Biotransformation: Levetiracetam is not extensively metabolized in humans. The major metabolic pathway (24% of the dose) is an enzymatic hydrolysis of the acetamide group. Hydrolysis of the acetamide group was measurable in a large number of tissues including blood cells. Two minor metabolites were also identified. One was obtained by hydroxylation of the pyrrolidone ring (1.6% of the dose) and the other one by opening of the pyrrolidone (0.9% of the dose).
Elimination: The plasma tin adults was 7±1 hr and did not vary either with dose, route of administration or repeated administration. The mean total body clearance was 0.96 mL/min/kg. The major route of excretion was via urine, accounting for a mean 95% of the dose (approximately 93% of the dose was excreted within 48 hrs). Excretion via feces accounted for only 0.3% of the dose. The cumulative urinary excretion of Levetiracetam and its primary metabolite accounted for 66 and 24% of the dose, respectively, during the 1st 48 hrs. The renal clearance of Levetiracetam and ucbL057 is 0.6 and 4.2 mL/min/kg, respectively, indicating that Levetiracetam is excreted by glomerular filtration with subsequent tubular reabsorption and that the primary metabolite is also excreted by active tubular secretion in addition to glomerular filtration. Levetiracetam elimination is correlated to creatinine clearance.
Elderly: In the elderly, the t_1/2 is increased by about 40% (10-11 hrs). This is related to the decrease in renal function.
Children (4-12 years): Following single dose administration (20 mg/kg) to epileptic children, the t_1/2 of Levetiracetam was 6 hrs. The apparent body clearance was 1.43 mL/min/kg. Following repeated oral dose administration (20-60 mg/kg/day) to epileptic children (4-12 years), Levetiracetam was rapidly absorbed. Peak plasma concentration was observed 0.5-1 hr after dosing. Linear & dose proportional increases were observed for C_max and AUC.
The elimination t_1/2 was approximately 5 hrs.
The apparent body clearance was 1.1 mL/min/kg.
Infants and Children (1 month to 4 years): Following single dose administration (20 mg/kg) of a 100 mg/mL oral son to epileptic children (1 month to 4 years), Levetiracetam was rapidly absorbed and C_max were observed approximately 1 hr after dosing. The pharmacokinetic results indicated that t_1/2 was shorter (5.3 hrs) than for adults (7.2 hrs) and apparent clearance was faster (1.5 mL/min/kg) than for adults (0.96 mL/min/kg).
Renal Impairment: The apparent body clearance of both Levetiracetam and its primary metabolite is correlated to the creatinine clearance. It is therefore recommended to adjust the maintenance daily dose of Levetiracetam, based on creatinine clearance in patients with moderate and severe renal impairment. In anuric end-stage renal disease the t_1/2 was approximately 25 and 3.1 hrs during interdialytic and intradialytic periods, respectively. The fractional removal of Levetiracetam was 51% during a typical 4-hr dialysis session.
Hepatic Impairment: In patients 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 patients, but decreased renal clearance accounted for most of the decreased.
Lepixa: 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 inter conversion 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 Dosage & Administration and Precautions).
Special Populations: Elderly: Pharmacokinetics of 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: Pharmacokinetics of levetiracetam were evaluated in 24 pediatric patients (age 6-12 years) after single dose (20 mg/kg). The body weight adjusted apparent clearance of levetiracetam was approximately 40% higher than in adults.
A repeat dose pharmacokinetic study was conducted in pediatric patients (age 4-12 years) at doses of 20 mg/kg/day, 40 mg/kg/day, and 60 mg/kg/day of the immediate release formulation of Levetiracetam. The evaluation of the pharmacokinetic profile of levetiracetam and its metabolite (ucb L057) in 14 pediatric patients demonstrated rapid absorption of levetiracetam at all doses with a T_max of about 1 hour and a t_½ of 5 hours across the three dosing levels. The pharmacokinetics of levetiracetam in children was linear between 20 to 60 mg/kg/day. The potential interaction of levetiracetam with other AEDs was also evaluated in these patients. Levetiracetam had no significant effect on the plasma concentrations of carbamazepine, valproic acid, topiramate or lamotrigine. However, there was about a 22% increase of apparent clearance of levetiracetam when it was co-administered with an enzyme-inducing AED (e.g. carbamazepine). Population pharmacokinetic analysis showed that body weight was significantly correlated to clearance of levetiracetam in pediatric patients; clearance increased with an increase in body weight.
Gender: Levetiracetam C_max and AUC were 20% higher in women (N=11) 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. Cross study comparisons involving Caucasians (N=12) and Asians (N=12), however, show that pharmacokinetics of 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 disposition of 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 >80 mL/min). Approximately 50% of the pool of levetiracetam in the body is removed during a standard 4-hour hemodialysis procedure (see Dosage Adjustments in Adult Renal Impairment under Dosage & Administration).
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.
Oral Solution: The pharmacokinetics of levetiracetam have been studied in healthy adult subjects, adults and pediatric patients with epilepsy, elderly subjects and subjects with renal and hepatic impairment.
Solution for injection: Equivalent doses of intravenous (IV) levetiracetam and oral levetiracetam result in equivalent C_max, C_min and total systemic exposure to levetiracetam when the IV levetiracetam is administered as a 15-minute infusion.
The pharmacokinetics of levetiracetam have been studied in healthy adult subjects, adults and pediatric patients with epilepsy, elderly subjects, and subjects with renal and hepatic impairment.
Overview: Levetiracetam is rapidly and almost completely absorbed after oral administration. Levetiracetam injection and tablets are bioequivalent. 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 6-8 hours. It is increased in the elderly (primarily due to impaired renal clearance) and in subjects with renal impairment.
Distribution: The equivalence of levetiracetam injection and the oral formulation was demonstrated in a bioavailability study of 17 healthy volunteers. In this study, levetiracetam 1500 mg was diluted in 100 mL 0.9% sterile saline solution and was infused over 15 minutes. The selected infusion rate provided plasma concentrations of levetiracetam at the end of the infusion period similar to those achieved at Tmax after an equivalent oral dose. It is demonstrated that levetiracetam 1500 mg intravenous infusion is equivalent to levetiracetam 3 x 500 mg oral tablets. The time independent pharmacokinetic profile of levetiracetam was demonstrated following 1500 mg intravenous infusion for 4 days with BID dosing. The AUC (0-12) at steady-state was equivalent to AUCinf following an equivalent single dose.
Levetiracetam and its major metabolite are less than 10% bound to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely.
Specific Populations: Pediatric Patients: Intravenous Formulation: A population pharmacokinetic analysis for the intravenous formulation was conducted in 49 pediatric patients (1 month to <16 years of age) weighing 3-79 kg. Patients received levetiracetam as a 15-minute IV infusion at doses between 14 mg/kg/day and 60 mg/kg/day twice daily. Plasma concentrations and model derived steady-state exposure AUC (0-12) were within the range of the exposure observed in pediatric patients receiving equivalent doses of the oral solution.
Following single dose administration (20 mg/kg) of a 10% oral solution to pediatric patients with epilepsy (1 month to <4 years), levetiracetam was rapidly absorbed and peak plasma concentrations were observed approximately 1 hour after dosing. Levetiracetam half-life in pediatric patients 1 month to <4 years with epilepsy was shorter (5.3 h) than in adults (7.2 h), and apparent clearance (1.5 mL/min/kg) was faster than in adults (0.96 mL/min/kg).
Pregnancy: Levetiracetam levels may decrease during pregnancy.
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 in the placebo-controlled clinical studies in epilepsy patients.
Phenytoin: Levetiracetam (3000 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: Levetiracetam (1500 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 Levetiracetam 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.
Effect of AEDs in Pediatric Patients: There was about a 22% increase of apparent total body clearance of levetiracetam when it was co-administered with enzyme-inducing AEDs. Dose adjustment is not recommended. Levetiracetam had no effect on plasma concentrations of carbamazepine, valproate, topiramate, or lamotrigine.
Oral Contraceptives: Levetiracetam (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: Levetiracetam (1000 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: Levetiracetam (1000 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 1000 mg twice daily. C^ss 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 Levetiracetam on probenecid was not studied.
Toxicology: Solution for injection: Carcinogenesis: Rats were dosed with levetiracetam in the diet for 104 weeks at doses of 50, 300 and 1800 mg/kg/day. The highest dose is 6 times the maximum recommended daily human dose (MRHD) of 3000 mg on a mg/m² basis and it also provided systemic exposure (AUC) approximately 6 times that achieved in humans receiving the MRHD. There was no evidence of carcinogenicity. In mice, oral administration of levetiracetam for 80 weeks (doses up to 960 mg/kg/day) or 2 years (doses up to 4000 mg/kg/day, lowered to 3000 mg/kg/day after 45 weeks due to intolerability) was not associated with an increase in tumors. The highest dose tested in mice for 2 years (3000 mg/kg/day) is approximately 5 times the MRHD on a mg/m² basis.
Mutagenesis: Levetiracetam was not mutagenic in the Ames test or in mammalian cells in vitro in the Chinese hamster ovary/HGPRT locus assay. It was not clastogenic in an in vitro analysis of metaphase chromosomes obtained from Chinese hamster ovary cells or in an in vivo mouse micronucleus assay. The hydrolysis product and major human metabolite of levetiracetam (ucb L057) was not mutagenic in the Ames test or the in vitro mouse lymphoma assay.
Impairment of Fertility: No adverse effects on male or female fertility or reproductive performance were observed in rats at oral doses up to 1800 mg/kg/day (6 times the maximum recommended human dose on a mg/m² or systemic exposure [AUC] basis).

Lepixa 500/Lepixa 1000: Monotherapy in the treatment of partial onset seizures with or without secondary generalization in patients from 16 years with newly diagnosed epilepsy.
As adjunctive therapy in the treatment of partial onset seizures with or without secondary generalization in adults and children from 4 years with epilepsy; myoclonic seizures in adults and adolescents from 12 years with juvenile myoclonic epilepsy.
Also as adjunctive therapy for patients ≥4 years with Primary Generalized Tonic, Clonic Seizure (PGTCS).
Lepixa: Oral Solution: Levetiracetam Oral Solution is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in patients from 16 years of age with newly diagnosed epilepsy.
Levetiracetam Oral Solution is indicated as adjunctive therapy: In the treatment of partial onset seizures with or without secondary generalisation in adults and children from 1 month of age with epilepsy.
In the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.
In the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy.
Levetiracetam Oral Solution concentrate is an alternative for patients (adults and children from 4 years of age) when oral administration is temporarily not feasible.
Solution for injection: Partial Onset Seizures: Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children 1 month of age and older with epilepsy. Levetiracetam injection is for intravenous use only as an alternative for patients when oral administration is temporarily is not feasible.
Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy: Levetiracetam is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy. Levetiracetam injection is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible.
Primary Generalized Tonic-Clonic Seizures: Levetiracetam is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy. Levetiracetam injection is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible.

Lepixa 500/Lepixa 1000: (See Table 7.)

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Dosage in children and adolescents ≥50 kg is the same as in adults. (See Table 8.)

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A 750-mg loading dose is recommended on the 1st day of treatment with Levetiracetam.
Following dialysis, a 250- to 500-mg supplemental dose is recommended.
Taken orally, swallowed with a sufficient quantity of liquid and may be taken with or without food. The daily dose is administered in 2 equally divided doses.
Monotherapy: Adults and Adolescents from 16 years: Recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after 2 weeks. The dose can be further increased by 250 mg twice daily every 2 weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.
Add-on therapy: Adults (>18 years) and Adolescents (12-17 years) of ≥50 kg: Initial Therapeutic Dose: 500 mg twice daily. This dose can be started on the 1st day of treatment.
Depending upon the clinical response and tolerance, the daily dose can be increased up to 1500 mg twice daily. Dose changes can be made in 500 mg twice-daily increases or decreases every 2-4 weeks.
Elderly (≥65 years): Adjustment of the dose is recommended in elderly patients with compromised renal function.
Children 4-11 years and Adolescents 12-17 years weighing <50 kg: The initial therapeutic dose is 10 mg/kg twice daily. Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every 2 weeks. The lowest effective dose should be used. Dosage in children ≥50 kg is the same as in adults. The physician should prescribe the most appropriate pharmaceutical form and strength according to weight and dose.
Infants and Children <4 years: Levetiracetam is not recommended for use in children <4 years due to insufficient data on safety and efficacy.
Patients with Renal Impairment: The daily dose must be individualized according to renal function. For adult patient, refer to Table 2 and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CL_cr) in ml/min is needed. The CL_cr in mL/min may be estimated from serum creatinine (mg/dL) determination using the following formula: (See Equation 2 as follows.)
For children with renal impairment, Levetiracetam dose needs to be adjusted based on the renal function as levetiracetam clearance is related to renal function. This recommendation is based on a study in adult renally impaired patients.
Patients with Hepatic Impairment: No dose adjustment is needed with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore, a 50% reduction of the daily maintenance dose is recommended when the creatinine is <70 mL/min.
Lepixa: Oral solution: Monotherapy for adults and adolescents from 16 years of age: The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.
Add-on therapy for adults (18 years) and adolescents (12 to 17 years) weighing 50 kg or more: The initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment.
Depending upon the clinical response and tolerability, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decreases every two to four weeks.
Hepatic impairment: No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore a 50% reduction of the daily maintenance dose is recommended when the creatinine clearance is <60 ml/min/1.73 m².
Paediatric Population: The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to weight and dose.
The safety and efficacy of Levetiracetam Oral Solution concentrate for solution for infusion in infants and children less than 4 years have not been established.
Monotherapy: The safety and efficacy of Levetiracetam Oral Solution in children and adolescents below 16 years as monotherapy treatment have not been established.
There are no data available.
Add-on therapy for infants aged from 6 to 23 months, children (2 to 11 years)and adolescents (12 to 17 years) weighing less than 50 kg: The initial therapeutic dose is 10mg/kg twice daily.
Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used.
Dose in children 50 kg or greater is the same as in adults.
Dose recommendations for infants from 6 months of age, children and adolescents: (See Table 9).

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Add-on therapy for infants from 1 month to less than 6 months: The tablet formulation is not adapted for use in infants under the age of 6 months. The oral solution is the formulation to use in infants.
The initial therapeutic dose is 7 mg/kg twice daily.
Infants should start the treatment with Levetiracetam Oral Solution 100 mg/ml oral solution.
Dose recommendations for infants less than 6 months: (See Table 10).

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This presentation should be prescribed for children older than 4 years, adolescents and adults.
A 150 ml bottle with graduated oral syringe containing up to 300 mg levetiracetam (corresponding to 3 ml) with a graduation every 0.1 ml (corresponding to 10 mg).
In order to ensure the accuracy of the dosing, the smaller bottle (150 ml) and syringe graduated from 0.1 to 3 ml per graduation of 0.1 ml should be prescribed for infants older than 6 months and young children.
A 150 ml bottle with graduated oral syringe containing up to 100 mg levetiracetam (corresponding to 1 ml) with a graduation every 0.05 ml (corresponding to 5 mg).
In order to ensure the accuracy of the dosing, the smaller bottle (150 ml) and syringe graduated from 0.05 to 1 ml per graduation of 0.05 ml should be prescribed for infants less than 6 months.
Method of Administration: The oral solution may be diluted in a glass of water and may be taken with or without food. A graduated oral syringe, an adaptor for the syringe and instructions for use in the package leaflet are provided with Levetiracetam Oral Solution 100 mg/mL.
The daily dose is administered in two equally divided doses.
Solution for injection: Dosing for Partial Onset Seizures: Adults 16 Years and Older: Initiate treatment with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg. There is no evidence that doses greater than 3000 mg/day confer additional benefit.
Pediatric Patients: 1 Month to <6 Months: Initiate treatment with a daily dose of 14 mg/kg in 2 divided doses (7 mg/kg twice daily). Increase the daily dose every 2 weeks by increments of 14 mg/kg to the recommended daily dose of 42 mg/kg (21 mg/kg twice daily). In the clinical trial, the mean daily dose was 35 mg/kg in this age group. The effectiveness of lower doses has not been studied.
6 Months to <4 Years: Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). Increase the daily dose in 2 weeks by an increment of 20 mg/kg to the recommended daily dose of 50 mg/kg (25 mg/kg twice daily). If a patient cannot tolerate a daily dose of 50 mg/kg, the daily dose may be reduced. In the clinical trial, the mean daily dose was 47 mg/kg in this age group.
4 Years to <16 Years: Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). Increase the daily dose every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced. In the clinical trial, the mean daily dose was 44 mg/kg. The maximum daily dose was 3000 mg/day.
Dosing for Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy: Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Increase the dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been studied.
Dosing for Primary Generalized Tonic-Clonic Seizures: Adults 16 Years and Older: Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Increase dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been adequately studied.
Pediatric Patients Ages 6 to <16 Years: Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). Increase the daily dose every 2 weeks by increments of 20 mg/kg (10 mg/kg twice daily) to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.
Switching from Oral Dosing: When switching from oral Levetiracetam, the initial total daily intravenous dosage of Levetiracetam should be equivalent to the total daily dosage and frequency of oral Levetiracetam.
Switching to Oral Dosing: At the end of the intravenous treatment period, the patient may be switched to Levetiracetam oral administration at the equivalent daily dosage and frequency of the intravenous administration.
Preparation and Administration Instructions: Levetiracetam injection is for intravenous use only and should be diluted in 100 mL of a compatible diluent prior to administration. If a smaller volume is required (e.g. pediatric patients), the amount of diluent should be calculated to not exceed a maximum levetiracetam concentration of 15 mg per mL of diluted solution. Consideration should also be given to the total daily fluid intake of the patient. Levetiracetam injection should be administered as a 15-minute IV infusion. One vial of Levetiracetam injection contains 500 mg levetiracetam (500 mg/5 mL).
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Product with particulate matter or discoloration should not be used.
Any unused portion of the Levetiracetam injection vial contents should be discarded.
Adults: See Table 11 for the recommended preparation and administration of Levetiracetam injection for adults to achieve a dose of 500 mg, 1000 mg, or 1500 mg. (See Table 11.)

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For example, to prepare a 1000 mg dose, dilute 10 mL of Levetiracetam injection in 100 mL of a compatible diluent and administer intravenously as a 15-minute infusion.
Pediatric Patients: When using Levetiracetam injection for pediatric patients, dosing is weight-based (mg per kg). The following calculation should be used to determine the appropriate daily dose of Levetiracetam injection for pediatric patients: (See Equation 1.)

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Dosage Adjustments in Adult Patients with Renal Impairment: Levetiracetam dosing must be individualized according to the patient's renal function status. Recommended dosage adjustments for adults with renal impairment are shown in Table 12. Information is unavailable for dosage adjustments in pediatric patients with renal impairment. In order to calculate the dose recommended for adult 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: (See Equations 2 and 3).
Then CLcr is adjusted for body surface area (BSA) as follows: (See Equation 2).

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Then CLcr is adjusted for body surface area (BSA) as follows: (See Equation 3 and Table 12).

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Symptoms: Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with Levetiracetam overdoses.
Treatment: After an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis. There is no specific antidote for Levetiracetam. Treatment of an overdose will be symptomatic and may include hemodialysis. The dialyzer extraction efficiency is 60% for Levetiracetam and 74% for the primary metabolite.
Lepixa: Solution for injection: Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans: The highest known dose of oral Levetiracetam received in the clinical development program was 6000 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 Levetiracetam overdoses in postmarketing use.
Management of Overdose: There is no specific antidote for overdose with Levetiracetam. 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.
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.

Hypersensitivity to Levetiracetam or other pyrrolidone derivatives or any of the excipients used in the formulation.
Use in Lactation: See Use in Pregnancy & Lactation section for further information.
Lepixa: Solution for injection: Levetiracetam is contraindicated in patients with a hypersensitivity to levetiracetam. Reactions have included anaphylaxis and angioedema (see Precautions).

Lepixa 1000: Suicide, suicidal attempts, suicidal ideation have been reported in patients treated with Levetiracetam.
Lepixa: Oral solution: Discontinuation: In accordance with current clinical practice, if Levetiracetam Oral Solution has to be discontinued it is recommended to withdraw it gradually (e.g. in adults and adolescents weighing more than 50 kg: 500 mg decreases twice daily every two to four weeks; in children and adolescents weighing less than 50 kg: dose decrease should not exceed 10 mg/kg twice daily every two weeks).
Renal insufficiency: The administration of Levetiracetam Oral Solution to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection.
Suicide: Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known.
Therefore patients should be monitored for signs of depression and/or suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.
Paediatric population: Available data in children did not suggest impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.
Excipients oral solution: Levetiracetam 100 mg/ml oral solution includes methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed). It also includes maltitol liquid; patients with rare hereditary problems of fructose intolerance should not take this medicinal product.

Lepixa 500/Lepixa 1000: In accordance with current clinical practice, if Levetiracetam has to be discontinued, it is recommended to withdraw it gradually (eg, in adults: 500 mg decreases twice-daily every 2-4 weeks, in children: dose decrease should not exceed 10 mg/kg twice daily every 2 weeks).
In a study reflecting clinical practice, the concomitant antiepileptic medication could be withdrawn in a limited number of patients who responded to Levetiracetam adjunctive therapy. Available data in children did not suggest impact on growth and puberty. However, long-term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.
An increase in seizure frequency of >25% has been reported in 14% of Levetiracetam-treated adult and pediatric patients with partial onset seizures, whereas it was reported in 26 and 21% of placebo-treated adult and pediatric patients, respectively.
The administration of Levetiracetam to patients with renal impairment may require dose adaptation. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed.
Due to possible different individual sensitivity, some patients might experience, especially at the beginning of treatment or following a dose increase, somnolence or other central nervous system related symptoms. Therefore, caution is recommended in those patients when performing skilled tasks eg, driving vehicles or operating machinery. Patients are advised not to drive or used machines until it is established that their ability to perform such activities is not affected.
Use in Pregnancy: See Use in Pregnancy & Lactation section for further information.
Lepixa: Oral Solution: Partial Onset Seizures: Adults: Minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 106 /mm³), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in levetiracetam-treated patients in controlled trials.
A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly 9 significant (≤2.8 x 10 /L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (≤1.0 x 190 /L) decreased neutrophil count. Of the treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts.
Juvenile Myoclonic Epilepsy: Although there were no obvious hematologic abnormalities observed in patients with JME, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients should be considered to be relevant for JME patients.
Hepatic Abnormalities: There were no meaningful changes in mean liver function tests (LFT) in controlled trials in adult or pediatric patients; lesser LFT abnormalities were similar in drug and placebo treated patients in controlled trials (1.4%). No adult or pediatric patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment.
Patients, their caregivers, and families should be counseled that AEDs, including levetiracetam, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Patients should be advised that levetiracetam may cause changes in behavior (e.g. aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability) and in rare cases patients may experience psychotic symptoms.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant. UCB, Inc. has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes associated with pregnant women being treated with all UCB antiepileptic drugs, including levetiracetam.
Laboratory Tests: Although most laboratory tests are not systematically altered with levetiracetam treatment, there have been relatively infrequent abnormalities seen in hematologic parameters and liver function tests.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Rats were dosed with levetiracetam in the diet for 104 weeks at doses of 50, 300 and 1800 mg/kg/day. The highest dose corresponds to 6 times the maximum recommended daily human dose (MRHD) of 3000 mg on a mg/m² basis and it also provided systemic exposure (AUC) approximately 6 times that achieved in humans receiving the MRHD. There was no evidence of carcinogenicity. A study was conducted in which mice received levetiracetam in the diet for 80 weeks at doses of 60, 240 and 960 mg/kg/day (high dose is equivalent to 2 times the MRHD on a mg/m² or exposure basis). Although no evidence for carcinogenicity was seen, the potential for a carcinogenic response has not been fully evaluated in that species because adequate doses have not been studied.
Mutagenesis: Levetiracetam was not mutagenic in the Ames test or in mammalian cells in vitro in the Chinese hamster ovary/HGPRT locus assay. It was not clastogenic in an in vitro analysis of metaphase chromosomes obtained from Chinese hamster ovary cells or in an in vivo mouse micronucleus assay. The hydrolysis product and major human metabolite of levetiracetam (ucb L057) was not mutagenic in the Ames test or the in vitro mouse lymphoma assay.
Impairment of Fertility: No adverse effects on male or female fertility or reproductive performance were observed in rats at doses up to 1800 mg/kg/day (approximately 6 times the maximum recommended human dose on a mg/m² or exposure basis).
Use In Patients With Impaired Renal Function: Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing hemodialysis. The dosage should be reduced in patients with impaired renal function receiving levetiracetam and supplemental doses should be given to patients after dialysis.
Effects on the Ability to Drive or Operate Machinery: Patients should be advised that levetiracetam may cause dizziness and somnolence. Accordingly, patients should be advised not to drive or operate machinery or engage in other hazardous activities until they have gained sufficient experience on levetiracetam to gauge whether it adversely affects their performance of these activities.
Use in Children: Minor, but statistically significant, decreases in WBC and neutrophil count were seen in levetiracetam-treated patients as compared to placebo. The mean decreases from baseline in the levetiracetam-treated group were -0.4 × 10⁹ /L and -0.3 × 10⁹/L, respectively, whereas there were small increases in the placebo group. Mean relative lymphocyte counts increased by 1.7% in levetiracetam-treated patients, compared to a decrease of 4% in placebo patients (statistically significant).
In the well-controlled trial, more levetiracetam-treated patients had a possibly clinically significant abnormally low WBC value (3.0% levetiracetam-treated versus 0% placebo), however, there was no apparent difference between treatment groups with respect to neutrophil count (5.0% levetiracetam-treated versus 4.2% placebo). No patient was discontinued secondary to low WBC or neutrophil counts.
Safety and effectiveness in patients below 4 years of age have not been established.
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 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric 2 dose of 60 mg/kg/day on a mg/m² basis) did not indicate a potential for age specific toxicity.
Use in the Elderly: Of the total number of subjects in clinical studies of levetiracetam, 347 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 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.
Solution for injection: Behavioral Abnormalities and Psychotic Symptoms: Levetiracetam may cause behavioral abnormalities and psychotic symptoms. Patients treated with Levetiracetam should be monitored for psychiatric signs and symptoms.
Behavioral abnormalities: In clinical studies using an oral formulation of Levetiracetam, 13% of adult Levetiracetam-treated patients and 38% of pediatric Levetiracetam-treated patients (4 to 16 years of age), compared to 6% and 19% of adult and pediatric placebo-treated patients, experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder).
A randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of an oral formulation of Levetiracetam as adjunctive therapy in pediatric patients (4 to 16 years of age). The results from an exploratory analysis indicated a worsening in Levetiracetam-treated patients on aggressive behavior (one of eight behavior dimensions), as measured in a standardized and systematic way using a validated instrument, the Achenbach Child Behavior Checklist (CBCL/6-18).
In clinical studies in pediatric patients 1 month to <4 years of age, irritability was reported in 12% of the Levetiracetam-treated patients compared to 0% of placebo-treated patients.
In clinical studies, 1.7% of adult Levetiracetam-treated patients discontinued treatment due to behavioral adverse reactions, compared to 0.2% of placebo-treated patients. The treatment dose was reduced in 0.8% of adult Levetiracetam-treated patients and in 0.5% of placebo-treated patients. Overall, 11% of Levetiracetam-treated pediatric patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6% of placebo-treated patients.
Psychotic symptoms: In clinical studies using an oral formulation of Levetiracetam, 1% of Levetiracetam-treated adult patients, 2% of Levetiracetam-treated pediatric patients 4 to 16 years of age, and 17% of Levetiracetam-treated pediatric patients 1 month to <4 years of age experienced psychotic symptoms, compared to 0.2%, 2%, and 5% in the corresponding age groups treated with placebo. In a controlled study that assessed the neurocognitive and behavioral effects of an oral formulation of Levetiracetam in pediatric patients 4 to 16 years of age, 1.6% of Levetiracetam-treated patients experienced paranoia, compared to 0% of placebo-treated patients. In the same study, 3.1% of Levetiracetam-treated patients experienced confusional state, compared to 0% of placebo treated patients (see Use in Children as follows).
In clinical studies, two (0.3%) Levetiracetam-treated adult patients were hospitalized, and their treatment was discontinued due to psychosis. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. There was no difference between drug- and placebo-treated patients in the incidence of the pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions.
Somnolence and Fatigue: Levetiracetam may cause somnolence and fatigue. Patients should be monitored for somnolence and fatigue, and be advised not to drive or operate machinery until they have gained sufficient experience on Levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery.
Somnolence: In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial onset seizures, 15% of Levetiracetam-treated patients reported somnolence, compared to 8% of placebo-treated patients. There was no clear dose response up to 3000 mg/day. In a study in which there was no titration, about 45% of patients receiving Levetiracetam 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of Levetiracetam-treated patients, compared to 0% in the placebo group. About 3% of Levetiracetam-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo treated patients. In 1.4% of Levetiracetam-treated patients and 0.9% of placebo-treated patients, the dose was reduced, while 0.3% of the Levetiracetam-treated patients were hospitalized due to somnolence.
Asthenia: In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial onset seizures, 15% of Levetiracetam-treated patients reported asthenia, compared to 9% of placebo-treated patients. Treatment was discontinued due to asthenia in 0.8% of Levetiracetam-treated patients as compared to 0.5% of placebo-treated patients. In 0.5% of Levetiracetam-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to asthenia.
Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment. In general, the incidences of somnolence and fatigue in the pediatric partial onset seizure studies, and in pediatric and adult myoclonic and primary generalized tonic-clonic studies were comparable to those of the adult partial onset seizure studies.
Anaphylaxis and Angioedema: Levetiracetam can cause anaphylaxis or angioedema after the first dose or at any time during treatment. Signs and symptoms in cases reported in the postmarketing setting have included hypotension, hives, rash, respiratory distress, and swelling of the face, lip, mouth, eye, tongue, throat, and feet. In some reported cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of anaphylaxis or angioedema, Levetiracetam should be discontinued and the patient should seek immediate medical attention.
Serious Dermatological Reactions: Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both pediatric and adult patients treated with Levetiracetam. The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. Recurrence of the serious skin reactions following rechallenge with Levetiracetam has also been reported. Levetiracetam should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.
Coordination Difficulties: Levetiracetam may cause coordination difficulties.
In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial onset seizures, 3.4% of Levetiracetam-treated patients experienced coordination difficulties, (reported as ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo-treated patients. A total of 0.4% of patients in controlled clinical studies discontinued Levetiracetam treatment due to ataxia, compared to 0% of placebo treated patients. In 0.7% of Levetiracetam-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to coordination difficulties, while one of the treated patients was hospitalized due to worsening of pre-existing ataxia. These events occurred most frequently within the first 4 weeks of treatment.
Patients should be monitored for signs and symptoms of coordination difficulties and advised not to drive or operate machinery until they have gained sufficient experience on Levetiracetam to gauge whether it could adversely affect their ability to drive or operate machinery.
Withdrawal Seizures: Antiepileptic drugs, including Levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency.
Hematologic Abnormalities: Levetiracetam can cause hematologic abnormalities. Hematologic abnormalities occurred in clinical trials and included decreases in red blood cells count (RBC), hemoglobin, and hematocrit, and increases in eosinophil counts. Decreased white blood cells count (WBC) and neutrophil counts also occurred in clinical trials. Cases of agranulocytosis have been reported in the postmarketing setting.
Partial Onset Seizures: Adults: In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial onset seizures, minor but statistically significant decreases compared to placebo in total mean RBC (0.03 x 10⁶/mm³), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in Levetiracetam-treated patients.
A total of 3.2% of Levetiracetam-treated and 1.8% of placebo-treated patients had at least one possibly significant (≤2.8 x 10⁹/L) decreased WBC, and 2.4% of Levetiracetam-treated and 1.4% of placebo-treated patients had at least one possibly significant (≤1.0 x 10⁹/L) decreased neutrophil count. Of the Levetiracetam-treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts.
Pediatric Patients 4 Years to <16 Years: In a controlled study in pediatric patients age 4 years to <16 years, statistically significant decreases in WBC and neutrophil counts were seen in Levetiracetam-treated patients, as compared to placebo. The mean decreases from baseline in the Levetiracetam-treated group were -0.4 × 10⁹/L and -0.3 × 10⁹/L, respectively, whereas there were small increases in the placebo group. Mean relative lymphocyte counts increased by 1.7% in Levetiracetam-treated patients, compared to a decrease of 4% in placebo-treated patients (statistically significant).
Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment. In general, the incidences of somnolence and fatigue in the pediatric partial onset seizure studies, and in pediatric and adult myoclonic and primary generalized tonic-clonic studies were comparable to those of the adult partial onset seizure studies.
In a randomized, double-blind, placebo-controlled study to assess the neurocognitive and behavioral effects of an oral formulation of Levetiracetam as adjunctive therapy in pediatric patients (4 to 16 years of age), 5 patients (8.6%) in the Levetiracetam-treated group and two patients (6.1%) in the placebo-treated group had high eosinophil count values that were possibly clinically significant (≥10% or ≥0.7 x 10⁹/L).
Increase in Blood Pressure: In a randomized, placebo-controlled study in patients 1 month to <4 years of age using an oral formulation of Levetiracetam, a significantly higher risk of increased diastolic blood pressure was observed in the Levetiracetam-treated patients (17%), compared to placebo-treated patients (2%). There was no overall difference in mean diastolic blood pressure between the treatment groups. This disparity between the Levetiracetam and placebo treatment groups was not observed in the studies of older children or in adults. Monitor patients 1 month to <4 years of age for increases in diastolic blood pressure.
Renal Impairment: Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance (see Pharmacology: Pharmacokinetics under Actions). Dosage adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis (see Dosage Adjustments in Adult Renal Impairment under Dosage & Administration).
Use in Pregnancy: See Use in Pregnancy & Lactation section for further information.
Use in Children: The safety and effectiveness of Levetiracetam in the adjunctive treatment of partial onset seizures in pediatric patients age 1 month to 16 years with epilepsy have been established (see Pharmacology: Clinical Studies: Partial Onset Seizures under Actions). The dosing recommendation in these pediatric patients varies according to age group and is weight-based (see Preparation and Administration Instructions under Dosage & Administration).
The safety and effectiveness of Levetiracetam as adjunctive treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established (see Pharmacology: Clinical Studies: Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy under Actions).
The safety and effectiveness of Levetiracetam as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in pediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established (see Pharmacology: Clinical Studies: Primary Generalized Tonic-Clonic Seizures under Actions).
A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of Levetiracetam as adjunctive therapy in 98 (Levetiracetam N=64, placebo N=34) pediatric patients, ages 4 years to 16 years, with partial seizures that were inadequately controlled. The target dose was 60 mg/kg/day. Neurocognitive effects were measured by the Leiter-R Attention and Memory (AM) Battery, which measures various aspects of a child's memory and attention. Although no substantive differences were observed between the placebo and drug treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority of 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, on average, a worsening in Levetiracetam-treated patients in aggressive behavior, one of the eight syndrome scores [see Behavioral Abnormalities and Psychotic Symptoms under Precautions].
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 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m² basis) did not indicate a potential for age-specific toxicity.
Use in the Elderly: There were 347 subjects in clinical studies of levetiracetam that were 65 years old 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 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 Pharmacology: Pharmacokinetics under Actions).

Use in Pregnancy: There are no adequate data from the use of Levetiracetam in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for human is unknown. Levetiracetam should not be used during pregnancy unless clearly necessary. Discontinuation of antiepileptic treatments may result in exacerbation of the disease, which is harmful to the mother and the fetus.
Labor and Delivery: The effect of Levetiracetam on labor and delivery in humans is unknown.
Use in Lactation: Levetiracetam is excreted in human breast milk. Therefore, breastfeeding is not recommended.
Levetiracetam is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Levetiracetam, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Lepixa: Solution for injection: Pregnancy: Levetiracetam blood levels may decrease during pregnancy (see Seizure Control During Pregnancy as follows).
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. Levetiracetam 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 3000 mg [MRHD] on a mg/m² basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/m² basis). The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m² 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/m² basis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1800 mg/kg/day (12 times the MRHD on a mg/m² basis). The developmental no effect dose was 200 mg/kg/day (equivalent to the MRHD on a mg/m² basis). Maternal toxicity was also observed at 1800 mg/k/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 3600 mg/kg/day (12 times the MRHD). 1200 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 during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m² basis).
Labor and Delivery: The effect of Levetiracetam on labor and delivery in humans is unknown.
Nursing Mothers: Levetiracetam is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Levetiracetam, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
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.

Lepixa 500/Lepixa 1000: Pooled safety data from clinical studies conducted with Levetiracetam oral formulation in adult patients with partial onset seizures showed that 46.4% of the patients in the levetiracetam group and 42% of the patients in the placebo group experienced undesirable effects. Serious undesirable effects were experienced. The most commonly reported undesirable effects were somnolence. asthenia and dizziness. There was no clear dose-response relationship, but incidence and severity of the central nervous system-related undesirable effects decreased overtime.
Pediatric patients (4-16 years) with partial onset seizures: The most common undesirable effects were somnolence, hostility, nervousness, emotional lability, agitation, anorexia, asthenia and headache.
Adults and Adolescents with myoclonic seizures (12-65 years): The most common undesirable effects were headache and somnolence. The incidence of undesirable effect in patients with myoclonic seizures was lower than that in adult patients with partial onset seizures.
Lepixa: Oral solution: Summary of the safety profile: Pooled safety data from clinical studies conducted with Levetiracetam Oral Solution oral formulations in adult patients with partial onset seizures showed that 46.4% of the patients in the Levetiracetam Oral Solution group and 42.2% of the patients in the placebo group experienced adverse reactions. Serious adverse reactions were experienced in 2.4% of the patients in the Levetiracetam Oral Solution and 2.0% of the patients in the placebo groups.
The most commonly reported adverse reactions were somnolence, asthenia and dizziness. In the pooled safety analysis, there was no clear dose response relationship but incidence and severity of the central nervous system related adverse reactions decreased over time.
In monotherapy 49.8% of the subjects experienced at least one drug related adverse reaction. The most frequently reported adverse reactions were fatigue and somnolence.
A study conducted in adults and adolescents with myoclonic seizures (12 to 65 years) showed that 33.3% of the patients in the Levetiracetam Oral Solution group and 30.0% of the patients in the placebo group experienced adverse reactions that were judged to be related to treatment. The most commonly reported adverse reactions were headache and somnolence. The incidence of adverse reactions in patients with myoclonic seizures was lower than that in adult patients with partial onset seizures (33.3% versus 46.4%).
A study conducted in adults and children (4 to 65 years) with idiopathic generalised epilepsy with primary generalised tonic-clonic seizures showed that 39.2% of the patients in the Levetiracetam Oral Solution group and 29.8% of the patients in the placebo group experienced undesirable effects that were judged to be related to treatment. The most commonly reported adverse reaction was fatigue.
An increase in seizure frequency of more than 25% was reported in 14% of levetiracetam treated adult and paediatric patients (4 to 16 years of age) with partial onset seizures, whereas it was reported in 26% and 21% of placebo treated adult and paediatric patients, respectively.
When Levetiracetam Oral Solution was used to treat primary generalised tonic-clonic seizures in adults and adolescents with idiopathic generalised epilepsy, there was no effect on the frequency of absences.
Adverse reactions that resulted from Levetiracetam Oral Solution intravenous use are similar to those associated with Levetiracetam Oral Solution oral use. The most frequently reported adverse reactions were dizziness, somnolence, headache and postural dizziness. Since there was limited exposure for Levetiracetam Oral Solution intravenous use and since oral and intravenous formulations are bioequivalent, the safety information of Levetiracetam Oral Solution intravenous will rely on Levetiracetam Oral Solution oral use.
Description of selected adverse reactions: The risk of anorexia is higher when topiramate is coadministered with levetiracetam.
In several cases of alopecia, recovery was observed when levetiracetam was discontinued.
Paediatric population: A study conducted in paediatric patients (4 to 16 years) with partial onset seizures showed that 55.4% of the patients in the Levetiracetam Oral Solution group and 40.2% of the patients in the placebo group experienced adverse reactions. Serious adverse reactions were experienced in none of the patients in the Levetiracetam Oral Solution group and 1.0% of the patients in the placebo group. The most commonly reported adverse reactions were somnolence, hostility, nervousness, emotional lability, agitation, anorexia, asthenia and headache in the paediatric population. Safety results in paediatric patients were consistent with the safety profile of levetiracetam in adults except for behavioural and psychiatric adverse reactions which were more common in children than in adults (38.6% versus 18.6%). However, the relative risk was similar in children as compared to adults.
Solution for injection: The following adverse reactions are discussed in more details in other sections of labeling: Behavioral Abnormalities and Psychotic Symptoms (see Precautions); Somnolence and Fatigue (see Precautions); Serious Dermatological Reactions (see Precautions); Coordination Difficulties (see Precautions); Hematologic Abnormalities (see Precautions); Increase in Blood Pressure (see 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 adverse reactions that result from Levetiracetam injection use include all of those reported for Levetiracetam tablets and oral solution. Equivalent doses of intravenous (IV) levetiracetam and oral levetiracetam result in equivalent C_max, C_min, and total systemic exposure to levetiracetam when the IV levetiracetam is administered as a 15-minute infusion.
Partial Onset Seizures: Adults: In controlled clinical studies using Levetiracetam tablets in adults with partial onset seizures, the most common adverse reactions in adult patients receiving Levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, asthenia, infection, and dizziness. Of the most common adverse reactions in adults experiencing partial onset seizures, asthenia, somnolence, and dizziness occurred predominantly during the first 4 weeks of treatment with Levetiracetam.
Table 13 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving Levetiracetam tablets in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either Levetiracetam or placebo was added to concurrent AED therapy. (See Table 13.)

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In controlled adult clinical studies using Levetiracetam tablets, 15% of patients receiving Levetiracetam and 12% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. (See Table 14.)

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Pediatric Patients 4 Years to <16 Years: The adverse reaction data presented as follows was obtained from a pooled analysis of two controlled pediatric clinical studies using an oral formulation in pediatric patients 4 to 16 years of age with partial onset seizures. The most common adverse reactions in pediatric patients receiving Levetiracetam in combination with other AEDs, for events with rates greater than placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability.
Table 15 lists adverse reactions from the pooled pediatric controlled studies (4 to 16 years of age) that occurred in at least 2% of pediatric Levetiracetam-treated patients and were numerically more common than in pediatric patients treated with placebo. In these studies, either Levetiracetam or placebo was added to concurrent AED therapy. (See Table 15.)

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In the controlled pooled pediatric clinical studies in patients 4-16 years of age, 7% of patients receiving Levetiracetam and 9% receiving placebo discontinued as a result of an adverse reaction.
Pediatric Patients 1 Month to <4 Years: In the 7-day controlled pediatric clinical study using an oral formulation of Levetiracetam in children 1 month to less than 4 years of age with partial onset seizures, the most common adverse reactions in patients receiving Levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence and irritability. Because of the shorter exposure period, incidences of adverse reactions are expected to be lower than in other pediatric studies in older patients. Therefore, other controlled pediatric data, presented previously, should also be considered to apply to this age group.
Table 16 lists adverse reactions that occurred in at least 5% of pediatric epilepsy patients (ages 1 month to <4 years) treated with Levetiracetam in the placebo-controlled study and were numerically more common than in patients treated with placebo. In this study, either Levetiracetam or placebo was added to concurrent AED therapy. (See Table 16.)

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In the 7-day controlled pediatric clinical study in patients 1 month to <4 years of age, 3% of patients receiving Levetiracetam and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. There was no adverse reaction that resulted in discontinuation for more than one patient.
Myoclonic Seizures: Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse reaction pattern for patients with JME is expected to be essentially the same as for patients with partial seizures.
In the controlled clinical study using Levetiracetam tablets in patients with myoclonic seizures, the most common adverse reactions in patients receiving Levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, neck pain, and pharyngitis.
Table 17 lists adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with Levetiracetam tablets and were numerically more common than in patients treated with placebo. In this study, either Levetiracetam or placebo was added to concurrent AED therapy. (See Table 17.)

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In the placebo-controlled study using Levetiracetam tablets in patients with JME, 8% of patients receiving Levetiracetam and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. The adverse reactions that led to discontinuation or dose reduction and that occurred more frequently in Levetiracetam-treated patients than in placebo-treated patients are presented in Table 18. (See Table 18.)

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Primary Generalized Tonic-Clonic Seizures: Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse reaction pattern for patients with primary generalized tonic-clonic (PGTC) seizures is expected to be essentially the same as for patients with partial seizures.
In the controlled clinical study that included patients 4 years of age and older with PGTC seizures, the most common adverse reaction in patients receiving Levetiracetam oral formulation in combination with other AEDs, for events with rates greater than placebo was nasopharyngitis.
Table 19 lists adverse reactions that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with Levetiracetam and were numerically more common than in patients treated with placebo. In this study, either Levetiracetam or placebo was added to concurrent AED therapy. (See Table 19.)

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In the placebo-controlled study, 5% of patients receiving Levetiracetam and 8% receiving placebo either discontinued or had a dose reduction during the treatment period as a result of an adverse reaction.
This study was too small to adequately characterize the adverse reactions that could be expected to result in discontinuation of treatment in this population. It is expected that the adverse reactions that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials (see Tables 14 and 18).
In addition, the following adverse reactions were seen in other controlled adult studies of Levetiracetam: balance disorder, disturbance in attention, eczema, memory impairment, myalgia, and blurred vision.
Comparison of Gender, Age and Race: The overall adverse reaction profile of Levetiracetam was similar between females and males. There are insufficient data to support a statement regarding the distribution of adverse reactions by age and race.
Postmarketing Experience: The following adverse reactions have been identified during post approval use of Levetiracetam. 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 following adverse reactions have been reported in patients receiving Levetiracetam worldwide. The listing is alphabetized: abnormal liver function test, 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 Levetiracetam use; recovery was observed in majority of cases where Levetiracetam was discontinued.

Lepixa: Oral solution: Antiepileptic medicinal products: Pre-marketing data from clinical studies conducted in adults indicate that Levetiracetam Oral Solution did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of Levetiracetam Oral Solution.
As in adults, there is no evidence of clinically significant medicinal product interactions in paediatric patients receiving up to 60 mg/kg/day levetiracetam.
A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 20% higher levetiracetam clearance in children taking enzyme-inducing antiepileptic medicinal products. Dose adjustment is not required.
Probenecid: Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite, but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low. It is expected that other medicinal products excreted by active tubular secretion could also reduce the renal clearance of the metabolite. The effect of levetiracetam on probenecid was not studied and the effect of levetiracetam on other actively secreted medicinal products, e.g. NSAIDs, sulfonamides and methotrexate, is unknown.
Antacids: No data on the influence of antacids on the absorption of levetiracetam are available.
Food and alcohol: The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced.
No data on the interaction of levetiracetam with alcohol are available.

Lepixa: Solution for injection: Compatibility and Stability: Levetiracetam injection was found to be physically compatible and chemically stable when mixed with the following diluents and antiepileptic drugs for at least 24 hours and stored in polyvinyl chloride (PVC) bags at controlled room temperature 15-30°C (59-86°F).
Diluents: Sodium chloride (0.9%) injection, USP; Lactated Ringer's injection; Dextrose 5% injection, USP.
Other Antiepileptic Drugs Lorazepam.
Diazepam Valproate sodium: There is no data to support the physical compatibility of Levetiracetam injection with antiepileptic drugs that are not listed as previously mentioned.

Lepixa 500: Store at temperatures not exceeding 25°C.
Lepixa 1000/Lepixa: Store at temperatures not exceeding 30°C.

Lepixa: Solution for injection: Suicidal Behavior and Ideation: Counsel patients, their caregivers, and/or families that antiepileptic drugs (AEDs), including Levetiracetam, may increase the risk of suicidal thoughts and behavior and advise patients to be alert for the emergence or worsening of symptoms of depression; unusual changes in mood or behavior; or suicidal thoughts, behavior, or thoughts about self-harm. Advise patients, their caregivers, and/or families to immediately report behaviors of concern to a healthcare provider.
Psychiatric Reactions and Changes in Behavior: Advise patients and their caregivers that Levetiracetam may cause changes in behavior (e.g., aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability) and psychotic symptoms.
Effects on Driving or Operating Machinery: Inform patients that Levetiracetam may cause dizziness and somnolence. Inform patients not to drive or operate machinery until they have gained sufficient experience on Levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery.
Dermatological Adverse Reactions: Advise patients that serious dermatological adverse reactions have occurred in patients treated with Levetiracetam and instruct them to call their physician immediately if a rash develops.
Pregnancy: Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during Levetiracetam therapy. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy (see Pregnancy under Use in Pregnancy & Lactation).

Anticonvulsants

N03AX14 - levetiracetam ; Belongs to the class of other antiepileptics.

Rx