LEVETIRACETAM (Page 6 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 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 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).

14 CLINICAL STUDIES

14.1 Partial Onset Seizures

Effectiveness in Partial Onset Seizures in Adults with Epilepsy
The effectiveness of Levetiracetam tablets 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 tablets 1000 mg/day (N=97), levetiracetam tablets 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 above. The 18-week treatment period consisted of a 6-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant. The primary measure of effectiveness 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 10.

Table 10: Reduction in Mean Over Placebo in Weekly Frequency of Partial Onset Seizures in Study 1

*statistically significant versus placebo
	Placebo(N=95)	Levetiracetam tablets1000 mg/day(N=97)	Levetiracetam tablets3000 mg/day(N=101)
Percent reduction in partial seizure frequency over placebo	–	26.1%*	30.1%*

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.

Figure 1: Responder Rate (≥50% Reduction from Baseline) in Study 1

*statistically significant versus placebo
Study 2 Study 2 was a double-blind, placebo-controlled, crossover study conducted at 62 centers in Europe comparing Levetiracetam tablets 1000 mg/day (N=106), levetiracetam tablets 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 above. The 16-week treatment period consisted of the 4-week titration period followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant. The primary measure of effectiveness 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 11.

Table 11: Reduction in Mean Over Placebo in Weekly Frequency of Partial Onset Seizures in Study 2: Period A

*statistically significant versus placebo
	Placebo (N=111)	Levetiracetam tablets1000 mg/day (N=106)	Levetiracetam tablets2000 mg/day (N=105)
Percent reduction in partial seizure frequency over placebo	–	17.1%*	21.4%*

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.

Figure 2: Responder Rate (≥50% Reduction from Baseline) in Study 2: Period A

*statistically significant versus placebo

The comparison of Levetiracetam tablets 2000 mg/day to Levetiracetam tablets 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 tablets 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 above. The 16-week treatment period consisted of a 4-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED doses were held constant. The primary measure of effectiveness was a between group comparison of the percent reduction in weekly seizure frequency relative to placebo over the 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 12 displays the results of the analysis of Study 3.

Table 12: Reduction in Mean Over Placebo in Weekly Frequency of Partial Onset Seizures in Study 3

*statistically significant versus placebo
	Placebo(N=104)	Levetiracetam tablets 3000 mg/day(N=180)
Percent reduction in partial seizure frequency over placebo	–	23.0%*

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.

Figure 3: Responder Rate (≥50% Reduction from Baseline) in Study 3

*statistically significant versus placebo

Effectiveness in Partial Onset Seizures in Pediatric Patients 4 Years to 16 Years with EpilepsyThe effectiveness of Levetiracetam tablets as adjunctive therapy (added to other antiepileptic drugs) in pediatric patients was established in one multicenter, randomized double-blind, placebo-controlled study (study 4), conducted at 60 sites in North America, in pediatric patients 4 to 16 years of age with partial seizures uncontrolled by standard antiepileptic drugs (AEDs). Eligible patients on a stable dose of 1-2 AEDs, who still experienced at least 4 partial onset seizures during the 4 weeks prior to screening, as well as at least 4 partial onset seizures in each of the two 4-week baseline periods, were randomized to receive either levetiracetam tablets or placebo. The enrolled population included 198 patients (Levetiracetam tablets N=101, placebo N=97) with refractory partial onset seizures, whether or not secondarily generalized. The study consisted of an 8-week baseline period and 4-week titration period followed by a 10-week evaluation period. Dosing was initiated at a dose of 20 mg/kg/day in two divided doses. During the treatment period, Levetiracetam tablets doses were adjusted in 20 mg/kg/day increments, at 2-week intervals to the target dose of 60 mg/kg/day. The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire 14-week randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥ 50% reduction from baseline in partial onset seizure frequency per week). Table 13 displays the results of this study.

Table 13: Reduction in Mean Over Placebo in Weekly Frequency of Partial Onset Seizures in Study 4

*statistically significant versus placebo
	Placebo(N=97)	Levetiracetam tablets (N=101)
Percent reduction in partial seizure frequency over placebo	–	26.8%*

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.

Figure 4: Responder Rate (≥ 50% Reduction from Baseline) in Study 4

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

Figure 5: Responder Rate For All Patients Ages 1 Month to < 4 Years (≥ 50% Reduction from Baseline) in Study 5

^* statistically significant versus placebo