Roweepra Tablets

ROWEEPRA is an antiepileptic drug available as 500 mg (yellow) tablets for oral administration.

The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C8H14N2O2 and its molecular weight is 170.21. Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs). It has the following structural formula:

Levetiracetam, USP is a white to off-white crystalline powder with a faint odor and a bitter taste. It is very soluble in water (104.0 g/100 mL). It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane. (Solubility limits are expressed as g/100 mL solvent.)

ROWEEPRA tablets contain the labeled amount of levetiracetam, USP. Inactive ingredients: colloidal silicon dioxide, corn starch, hypromellose, lactose monohydrate, magnesium stearate, povidone, titanium dioxide, triacetin and iron oxide yellow.

The following adverse reactions are discussed in more details in other sections of labeling:

• Psychiatric Symptoms [see WARNINGS AND PRECAUTIONS]
• Suicidal Behavior and Ideation [see WARNINGS AND PRECAUTIONS]
• Somnolence and Fatigue [see WARNINGS AND PRECAUTIONS]
• Serious Dermatological Reactions [see WARNINGS AND PRECAUTIONS]
• Coordination Difficulties [see WARNINGS AND PRECAUTIONS]
• Hematologic Abnormalities [see WARNINGS AND PRECAUTIONS]
• Increase in Blood Pressure [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Partial Onset Seizures

Adults

In controlled clinical studies in adults 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, 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 3 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving levetiracetam 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.

Table 3: Adverse Reactions in Pooled Placebo-Controlled, Add-On Studies in Adults Experiencing Partial Onset Seizures

	Levetiracetam (N=769) %	Placebo (N=439) %
Asthenia	15	9
Somnolence	15	8
Headache	14	13
Infection	13	8
Dizziness	9	4
Pain	7	6
Pharyngitis	6	4
Depression	4	2
Nervousness	4	2
Rhinitis	4	3
Anorexia	3	2
Ataxia	3	1
Vertigo	3	1
Amnesia	2	1
Anxiety	2	1
Cough Increased	2	1
Diplopia	2	1
Emotional Lability	2	0
Hostility	2	1
Paresthesia	2	1
Sinusitis	2	1

In controlled adult clinical studies, 15% of patients receiving levetiracetam and 12% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. Table 4 lists the most common (>1%) adverse reactions that resulted in discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients.

Table 4: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in Placebo-Controlled Studies in Adult Patients Experiencing Partial Onset Seizures

Adverse Reaction	Levetiracetam (N=769) %	Placebo (N=439) %
Somnolence	4	2
Dizziness	1	0

Pediatric Patients 4 Years to <16 Years

The adverse reaction data presented below was obtained from a pooled analysis of two controlled pediatric clinical studies 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 5 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.

Table 5: Adverse Reactions in Pooled Placebo-Controlled, Add-On Studies in Pediatric Patients Ages 4 to 16 Years Experiencing Partial Onset Seizures

	Levetiracetam (N=165) %	Placebo (N=131) %
Headache	19	15
Nasopharyngitis	15	12
Vomiting	15	12
Somnolence	13	9
Fatigue	11	5
Aggression	10	5
Cough	9	5
Nasal Congestion	9	2
Upper Abdominal Pain	9	8
Decreased Appetite	8	2
Abnormal Behavior	7	4
Dizziness	7	5
Irritability	7	1
Pharyngolaryngeal Pain	7	4
Diarrhea	6	2
Lethargy	6	5
Insomnia	5	3
Agitation	4	1
Anorexia	4	3
Head Injury	4	0
Altered Mood	3	1
Constipation	3	1
Contusion	3	1
Depression	3	1
Fall	3	2
Influenza	3	1
Affect Lability	2	1
Anxiety	2	1
Arthralgia	2	0
Confusional State	2	0
Conjunctivitis	2	0
Ear Pain	2	1
Gastroenteritis	2	0
Joint Sprain	2	1
Mood Swings	2	1
Neck Pain	2	1
Rhinitis	2	0
Sedation	2	1

In 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 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 above, should also be considered to apply to this age group.

Table 6 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.

Table 6: Adverse Reactions in a Placebo-Controlled, Add-On Study in Pediatric Patients Ages 1 Month to < 4 Years Experiencing Partial Onset Seizures

	Levetiracetam (N=60) %	Placebo (N=56) %
Somnolence	13	2
Irritability	12	0

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 in patients 12 years of age and older 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 7 lists adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic 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.

Table 7: Adverse Reactions in a Placebo-Controlled, Add-On Study in Patients 12 Years of Age and Older with Myoclonic Seizures

	Levetiracetam (N=60) %	Placebo (N=60) %
Somnolence	12	2
Neck pain	8	2
Pharyngitis	7	0
Depression	5	2
Influenza	5	2
Vertigo	5	3

In the placebo-controlled study, 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 8.

Table 8: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in a Placebo-Controlled Study in Patients with Juvenile Myoclonic Epilepsy

Adverse Reaction	Levetiracetam (N=60) %	Placebo (N=60) %
Anxiety	3	2
Depressed mood	2	0
Depression	2	0
Diplopia	2	0
Hypersomnia	2	0
Insomnia	2	0
Irritability	2	0
Nervousness	2	0
Somnolence	2	0

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 in combination with other AEDs, for events with rates greater than placebo, was nasopharyngitis.

Table 9 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.

Table 9: Adverse Reactions in a Placebo-Controlled, Add-On Study in Patients 4 Years of Age and Older with PGTC Seizures

	Levetiracetam (N=79) %	Placebo (N=84) %
Nasopharyngitis	14	5
Fatigue	10	8
Diarrhea	8	7
Irritability	6	2
Mood swings	5	1

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 4 and 8).

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 postapproval 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 marketed 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.

Signs, Symptoms And Laboratory Findings Of Acute Overdosage In Humans

The highest known dose of levetiracetam received in the clinical development program was 6,000 mg/day. Other than drowsiness, there were no adverse reactions in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with 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.

Mechanism Of Action

The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown. The antiepileptic activity of levetiracetam was assessed in a number of animal models of epileptic seizures. Levetiracetam did not inhibit single seizures induced by maximal stimulation with electrical current or different chemoconvulsants and showed only minimal activity in submaximal stimulation and in threshold tests. Protection was observed, however, against secondarily generalized activity from focal seizures induced by pilocarpine and kainic acid, two chemoconvulsants that induce seizures that mimic some features of human complex partial seizures with secondary generalization. Levetiracetam also displayed inhibitory properties in the kindling model in rats, another model of human complex partial seizures, both during kindling development and in the fully kindled state. The predictive value of these animal models for specific types of human epilepsy is uncertain.

In vitro and in vivo recordings of epileptiform activity from the hippocampus have shown that levetiracetam inhibits burst firing without affecting normal neuronal excitability, suggesting that levetiracetam may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity.

Levetiracetam at concentrations of up to 10 μM did not demonstrate binding affinity for a variety of known receptors, such as those associated with benzodiazepines, GABA (gamma-aminobutyric acid), glycine, NMDA (N-methyl-D-aspartate), re-uptake sites, and second messenger systems. Furthermore, in vitro studies have failed to find an effect of levetiracetam on neuronal voltage-gated sodium or T-type calcium currents and levetiracetam does not appear to directly facilitate GABAergic neurotransmission. However, in vitro studies have demonstrated that levetiracetam opposes the activity of negative modulators of GABA- and glycine-gated currents and partially inhibits N-type calcium currents in neuronal cells.

A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam. Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis. Although the molecular significance of levetiracetam binding to SV2A is not understood, levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated with the potency of their antiseizure activity in audiogenic seizure-prone mice. These findings suggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug.

Pharmacodynamics

Effects on QTc Interval

The 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 (1,000 mg or 5,000 mg) in 52 healthy subjects. The upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 milliseconds. Therefore, there was no evidence of significant QTc prolongation in this study.

Pharmacokinetics

Absorption And Distribution

Absorption of levetiracetam is rapid, with peak plasma concentrations occurring in about an hour following oral administration in fasted subjects. The oral bioavailability of levetiracetam tablets is 100% and the tablets and oral solution are bioequivalent in rate and extent of absorption. Food does not affect the extent of absorption of levetiracetam but it decreases Cmax by 20% and delays Tmax by 1.5 hours. The pharmacokinetics of levetiracetam are linear over the dose range of 500-5,000 mg. Steady state is achieved after 2 days of multiple twice-daily dosing. 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.

Metabolism

Levetiracetam is not extensively metabolized in humans. The major metabolic pathway is the enzymatic hydrolysis of the acetamide group, which produces the carboxylic acid metabolite, ucb L057 (24% of dose) and is not dependent on any liver cytochrome P450 isoenzymes. The major metabolite is inactive in animal seizure models. Two minor metabolites were identified as the product of hydroxylation of the 2-oxo-pyrrolidine ring (2% of dose) and opening of the 2-oxo-pyrrolidine ring in position 5 (1% of dose). There is no enantiomeric interconversion of levetiracetam or its major metabolite.

Elimination

Levetiracetam plasma half-life in adults is 7 ± 1 hour and is unaffected by either dose or repeated administration. Levetiracetam is eliminated from the systemic circulation by renal excretion as unchanged drug which represents 66% of administered dose. The total body clearance is 0.96 mL/min/kg and the renal clearance is 0.6 mL/min/kg. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. The metabolite ucb L057 is excreted by glomerular filtration and active tubular secretion with a renal clearance of 4 mL/min/kg. Levetiracetam elimination is correlated to creatinine clearance. Levetiracetam clearance is reduced in patients with renal impairment [see Use In Specific Populations and DOSAGE AND ADMINISTRATION].

Specific 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. 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 Tmax of about 1 hour and a t1/2 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).

Following single dose administration (20 mg/kg) of a 10% oral solution to children with epilepsy (1 month to < 4 years), levetiracetam was rapidly absorbed and peak plasma concentrations were observed approximately 1 hour after dosing. The pharmacokinetic results indicated that half-life was shorter (5.3 h) than for adults (7.2 h) and apparent clearance was faster (1.5 mL/min/kg) than for adults (0.96 mL/min/kg).

Population pharmacokinetic analysis showed that body weight was significantly correlated to the clearance of levetiracetam in pediatric patients; clearance increased with an increase in body weight.

Pregnancy

Levetiracetam levels may decrease during pregnancy.

Gender

Levetiracetam Cmax 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 AND 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.

Drug Interactions

In vitro data on metabolic interactions indicate that levetiracetam is unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above Cmax levels achieved within the therapeutic dose range, are neither inhibitors of, nor high affinity substrates for, human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.

Potential pharmacokinetic interactions of or with levetiracetam were assessed in clinical pharmacokinetic studies (phenytoin, valproate, warfarin, digoxin, oral contraceptive, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients.

Phenytoin

Levetiracetam (3,000 mg daily) had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. Pharmacokinetics of levetiracetam were also not affected by phenytoin.

Valproate

Levetiracetam (1,500 mg twice daily) did not alter the pharmacokinetics of valproate in healthy volunteers. Valproate 500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion. There also was no effect on exposure to and the excretion of the primary metabolite, ucb L057.

Other Antiepileptic Drugs

Potential drug interactions between 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 (1,000 mg twice daily) did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every day. Coadministration of digoxin did not influence the pharmacokinetics of levetiracetam.

Warfarin

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

Probenecid

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

Clinical Studies

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, 1,000 mg, 2,000 mg, or 3,000 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 1,000 mg/day (N=97), levetiracetam 3,000 mg/day (N=101), and placebo (N=95) given in equally divided doses twice daily. After a prospective baseline period of 12 weeks, patients 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

	Placebo (N=95)	Levetiracetam 1,000 mg/day (N=97)	Levetiracetam 3,000 mg/day (N=101)
Percent reduction in partial seizure frequency over placebo	-	26.1%*	30.1%*
*statistically significant versus placebo

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

Study 2

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

The first period of the study (Period A) was designed to be analyzed as a parallel-group study. After a prospective baseline period of up to 12 weeks, patients 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

	Placebo (N=111)	Levetiracetam 1,000 mg/day (N=106)	Levetiracetam 2,000 mg/day (N=105)
Percent reduction in partial seizure frequency over placebo	-	17.1%*	21.4%*
*statistically significant versus placebo

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

The comparison of levetiracetam 2,000 mg/day to levetiracetam 1,000 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 3,000 mg/day (N=180) and placebo (N=104) in patients with refractory partial onset seizures, with or without secondary generalization, receiving only one concomitant AED. Study drug was given in two divided doses. After a prospective baseline period of 12 weeks, patients 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 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 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

	Placebo (N=104)	Levetiracetam 3,000 mg/day (N=180)
Percent reduction in partial seizure frequency over placebo	-	23.0%*
*statistically significant versus placebo

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

Effectiveness In Partial Onset Seizures In Pediatric Patients 4 Years To 16 Years With Epilepsy

The effectiveness of levetiracetam 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 or placebo. The enrolled population included 198 patients (levetiracetam 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 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

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

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

Effectiveness In Partial Onset Seizures In Pediatric Patients 1 Month To <4 Years With Epilepsy

The effectiveness of levetiracetam 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 pediatric patients 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 or placebo. The enrolled population included 116 patients (levetiracetam 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), 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). The study consisted of a 5-day evaluation period which included a 1-day titration period followed by a 4-day maintenance period. 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 effectiveness 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. A total of 109 patients were included in the efficacy analysis. A statistically significant difference between levetiracetam and placebo was observed (see Figure 5). The treatment effect associated with levetiracetam 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

Myoclonic Seizures In Patients With Juvenile Myoclonic Epilepsy

Effectiveness Of Myoclonic Seizures In Patients ≥12 Years Of Age With Juvenile Myoclonic Epilepsy (JME)

The effectiveness of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in patients 12 years of age and older with juvenile myoclonic epilepsy (JME) experiencing myoclonic seizures was established in one multicenter, randomized, double-blind, placebo-controlled study (Study 6), conducted at 37 sites in 14 countries. Of the 120 patients enrolled, 113 had a diagnosis of confirmed or suspected JME. 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 3,000 mg/day and treated at a stable dose of 3,000 mg/day over 12 weeks (evaluation period). Study drug was given in 2 divided doses.

The primary measure of effectiveness 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 14 displays the results for the 113 patients with JME in this study.

Table 14: Responder Rate (≥50% Reduction from Baseline) in Myoclonic Seizure Days per Week for Patients with JME in Study 6

	Placebo (N=59)	Levetiracetam (N=54)
Percentage of responders	23.7%	60.4%*
*statistically significant versus placebo

Primary Generalized Tonic-Clonic Seizures

Effectiveness In Primary Generalized Tonic-Clonic Seizures In Patients ≥6 Years Of Age

The effectiveness of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in patients 6 years of age and older with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic (PGTC) seizures was established in one multicenter, randomized, double-blind, placebo-controlled study (Study 7), 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 3,000 mg/day for adults or a pediatric target dose of 60 mg/kg/day and treated at a stable dose of 3,000 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 effectiveness 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 (predominately 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.

Table 15: Median Percent Reduction from Baseline in PGTC Seizure Frequency per Week in Study 7

	Placebo (N=84)	Levetiracetam (N=78)
Percent reduction in PGTC seizure frequency	44.6%	77.6%*
*statistically significant versus placebo

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.

Figure 6: Responder Rate (≥50% Reduction from Baseline) in PGTC Seizure Frequency per Week in Study 7

• Carbatrol
• Dilantin
• Dilantin 125
• Dilantin Infatabs
• Dilantin Kapseals
• Epitol

• Equetro
• Felbatol
• Tegretol
• Topamax
• Trokendi XR

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