KEPPRA® (levetiracetam)
`
`
`
`
`250 mg, 500 mg, 750 mg, and 1000 mg tablets
`100 mg/mL oral solution
`
`
`
`
`
`
`Rx only
`
`DESCRIPTION
`
`KEPPRA is an antiepileptic drug available as 250 mg (blue), 500 mg (yellow), 750 mg (orange),
`and 1000 mg (white) tablets and as a clear, colorless, grape-flavored liquid (100 mg/mL) 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 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.)
`
`KEPPRA tablets contain the labeled amount of levetiracetam. Inactive ingredients: colloidal
`silicon dioxide, croscarmellose sodium, magnesium stearate, polyethylene glycol 3350,
`polyethylene glycol 6000, polyvinyl alcohol, talc, titanium dioxide, and additional agents listed
`below:
`
`
`250 mg tablets: FD&C Blue #2/indi go carmine aluminum lake
`500 mg tablets: iron oxide yellow
`750 mg tablets: FD&C yellow #6/sunset yellow FCF aluminum lake, iron oxide red
`
`
`
`KEPPRA oral solution contains 100 mg of levetiracetam per mL. Inactive ingredients:
`ammonium glycyrrhizinate, citric acid monohydrate, glycerin, maltitol solution, methylparaben,
`potassium acesul fame, propylparaben, purified water, sodium citrate dihydrate and natural and
`
`artificial flavor.
`
`
`
`Page 1 of 34
`
`ARGENTUM Exhibit 1204
`Argentum Pharmaceuticals LLC v. Research Corporation Technologies, inc.
`IPR2016-00204
`
`Page 00001
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`

`
`CLINICAL PHARMACOLOGY
`
`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 benzodiazepin es, GABA (gamma­
`aminobutyric acid), glycine, NMDA (N-methyl-D-aspartate), re-uptake sites, and second
`messenger systems. Furthermore, in vitro studies have failed to find an effect of levetiracetam on
`
`neuronal voltage-gated sodium or T-type calcium currents and levetiracetam does not appear to
`directly facilitate GABAergic neurotransmission. However, in vitro studies have demonstrated
`
`that levetiracetam opposes the activity of negative modulators of GABA- and glycine-gated
`currents and partially inhibits N-type calcium currents in neuronal cells.
`
`A saturable and stereoselective neuronal binding site in rat brain tissue has been described for
`levetiracetam. Experimental data indicate that this binding site is the synaptic vesicle protein
`SV2A, thought to be involved in the regulation of vesicle exocytosis. Although the molecular
`
`significance of levetiracetam binding to synaptic vesicle protein SV2A is not understood,
`levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated
`
`with the potency of their antiseizure activity in audiogenic seizure-prone mice. These findings
`suggest that the interaction of levetiracetam with the SV2A protein may contribute to the
`
`antiepileptic mechanism of action of the drug.
`
`
`
`
`
`Pharmacokinetics
`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 tablets and oral solution are bioequivalent. The pharmacokinetics are linear and
`
`
`
`Page 2 of 34
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`Page 00002
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`
` time-invariant, with low intra- and inter-subject variability. The extent of bioavailability of
`
`levetiracetam is not affected by food. 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.
`
`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
`
`5000 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 meta bolized 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 clearan ce 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 Special Populations, Renal Impairment and
`DOSAGE AND ADMINISTRATION, Adult Patients with Impaired Renal Function).
`
`Pharmacokinetic Interactions
`In vitro data on metabolic interactions indicate that levetiracetam is unlikely to produce, or be
`
`its major metabolite, at
`subject
`to, pharmacokinetic
`interactions. Levetiracetam and
`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 ad dition, levetiracetam does not affect the in
`
`
`vitro glucuronidation of valproic acid.
`
`
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`Page 3 of 34
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`Page 00003
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`
`Potential pharmacokinetic interactions of or with levetiracetam were assessed in clinical
`pharmac okinetic studies (phenytoin, valproate, warfarin, digoxin, oral contraceptive, probenecid)
`and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy
`patients (see PRECAUTIONS, Drug Interactions).
`
`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. T his 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 AE Ds was also evaluated in
`these patients (see PRECAUTIONS, Drug Interactions). 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. carbamazepin e). 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 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 pharmacokin etic 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.
`
`
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`Page 4 of 34
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`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 >80mL/min). Approximately 50% of the pool of levetiracetam in the body
`is removed during a standard 4-hour hemodialysis procedure.
`
`Dosage should be reduced in patients with impaired renal function receiving levetiracetam, and
`supplemental doses should be given to patients after dialysis (see PRECAUTIONS and
`DOSAGE AND ADM INISTRATION, Adult Patients with Impaired Renal Function).
`
`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 impa irment
`(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 nee ded for patients with
`hepatic impairment.
`
`
`
`CLINICAL STUDIES
`
`In the following studies, statistical significance versus placebo indicates a p value < 0.05.
`
`Effectiveness In Partial Onset Seizures In Adults With Epilepsy
`The effectiveness of KEPPRA 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 KEPPRA 1000 mg/day (N=97), KEPPRA 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 tr eatment groups described above. The
`18-week treatment period consisted of a 6-week titration period, followed by a 12-week fixed
`
`
`
`Page 5 of 34
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`Page 00005
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`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
`( tration + evaluation period) . Second ary outcome varia bles included the responder rate
`ti
`(incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency). The
`results of the analysis of Study 1 are displayed in T able 1.
`
`
`Table 1: Reduction In Mean Over Placebo In Weekly Frequency Of Partial Onset Seizures In
`Study 1
`
`
`
`Percent reduction in partial
`seizure frequency over
`placebo
`*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
`
`
`
`37.1%
`
`*
`
`39.6%
`
`*
`
`45%
`
`40%
`
`35%
`
`30%
`
`25%
`
`20%
`
`15%
`
`10%
`
`5%
`
`0%
`
`7.4%
`
` of Patients
`
`%
`
`
`
`Placebo (N=95)
`
`KEPPRA 1000 mg/day KEPPRA 3000 mg/day
`
`(N=97)
`(N=101)
`
`
`*statistically significant versus placebo
`
`
`
`Study 2
`
`Study 2 was a double-blind, placebo-controlled, crossover study conducted at 62 centers in
`
`Europe comparing KEPPRA 1000 mg/day (N=106), KEPPRA 2000 mg/day (N=105), and
`placebo (N=111) given in equally divided doses twice daily.
`
`Page 6 of 34
`
`
`
`
`
`
`Placebo
`(N=95)
`
`–
`
`KEPPRA
`1000 mg/day
`(N=97)
`
`26.1%*
`
`KEPPRA
`
`3000 mg/day
`(N=101)
` 30.1%*
`
`Page 00006
`
`

`
`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
`
`v riables included the responder r ate (incid ence of patients with ≥50% reduction from baseline a
`in partial onset seizure frequency). The results of the analysis of Period A are displayed in Table
`
`2.
`
`
`Table 2: Reduction In Mean Over Placebo In Weekly Frequency Of Part ial Onset Seizu res In
`Study 2: Period A
`
`
`
`
`
`Placebo
`(N=111)
`
`–
`
`Percent reduction in partial
`seizure frequency over
`placebo
`*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
`
`
`
`
`KEPPRA
`1000 mg/day
`(N=106)
`
`17.1%*
`
`KEPPRA
`2000 mg/day
`(N=105)
`
`21.4%*
`
`35.2%
`
`*
`
`20.8%
`
`*
`
`6.3%
`
`Placebo (N=111)
`
`
`KEPPRA 1000 mg/day KEPPRA 2000 mg/day
`
`(N=105)
`
`(N=106)
`
`45%
`
`40%
`
`35%
`
`30%
`
`25%
`
`20%
`
`15%
`
`10%
`
`5%
`
`0%
`
`% of Patients
`
`
`
`*statistically significant versus placebo
`
`
`
`
`The comparison of KEPPRA 2000 mg/day to KEPPRA 1000 mg/day for responder rate was
`statistically significant (P=0.02). Analysis of the trial as a cross-over yielded similar results.
`
`
`
`Page 7 of 34
`
`Page 00007
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`

`
`Study 3
`Study 3 was a double-blind, placebo-controlled, parallel-group study conducted at 47 centers in
`
`Europe comparing KEPPRA 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 entire randomi zed treatment period
`(titration + evaluation period). Secon dary outcome variables included the responder rate
`(incidence of patients with ≥50% reduction from baseline in partia l onset seizure frequency).
`Table 3 displays the results of the analysis of Study 3.
`
`Table 3: Reduction In Mean Over Placebo In Weekly Frequency Of Partial Onset Seizures In
`
`Study 3
`
`
`
`
`
`Placebo
`(N=104)
`
`KEPPRA
`3000 mg/day
`(N=180)
`
`23.0%*
`
`–
`
`Percent reduction in partial seizure
`frequency over placebo
`*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
`
`
`
`39.4%
`
`*
`
`14.4%
`
`Placebo (N=104)
`
`KEPPRA 3000 mg/day (N=180)
`
`*statistically significant versus placebo
`
`
`
`Page 8 of 34
`
`
`45%
`
`40%
`
`35%
`
`30%
`
`25%
`
`20%
`
`15%
`
`10%
`
`5%
`
`0%
`
`% of Patients
`
`
`
`Page 00008
`
`

`
`Effectiveness In Partial Onset Seizures In Pediatric Patients With Epilepsy
`The effectiveness of KEPPRA as adjunctive therapy (added to other antiepileptic drugs) in
`
`pediatric patients was established in one multicenter, randomized double-blind, placebo-
`controlled study, conducted at 60 sites in North America, in children 4 to 16 years of age with
`partial seizures uncontrolled by standard antiepileptic drugs (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 KEPPRA or placebo. The enrolled population
`
`included 198 patients (KEPPRA 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, KEPPRA doses were ad justed
`
`in 20 mg/kg/day increments, at 2-week intervals to the target dose of 60 mg/kg/day. The pr imary
`measure of effectiveness was a between group comparison of the percent reduction in weekly
`
`p rtial seizure frequency relative to p a lacebo over the entire 14-week randomized treatment
`
`period (titration + evaluation period). Secondary outcome variable s included the responder rate
`(incidence of patients with ≥ 50% reduction from baselin e in parti al onset seizure frequency per
`week). Table 4 displays the results of this study.
`
`Table 4: Reduction In Mean Over Placebo In Weekly Frequency Of Partial Onset Seizures
`
`
`
`
`
`Percent reduction in partial seizure
`frequency over placebo
`*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)
`
`
`
`Placebo
`(N=97)
`-
`
`KEPPRA
`(N=101)
`
`26.8%*
`
`
`
`Page 9 of 34
`
`Page 00009
`
`

`
`44.6%
`
`*
`
`19.6%
`
`45%
`
`40%
`
`35%
`
`30%
`
`25%
`
`20%
`
`15%
`
`10%
`
`5%
`
`0%
`
`% of Patients
`
`
`
`Placebo (N=97)
`
`KEPPRA (N=101)
`
`*statistically significant versus placebo
`
`
`
`Effectiveness In Myoclonic Seizures In Patients ≥12 Years Of Age With Juvenile
`Myoclonic Epilepsy (JME)
`The effectiveness of KEPPRA 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, conducted at 37 sites in 14 countries. Of the 12 0 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 KEPPRA or placebo (KEPPRA
`N=60, placebo N=60). Patients were tit rated 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 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 5 displays the results for the 113
`
`patients with JME in this study.
`
`
`Table 5: Responder Rate (≥50% Reduction From Baseline) In Myoclonic Seizure Days Per
`Week for Patients with JME
`
`
`
`
`Placebo
`(N=59)
`23.7%
`
`KEPPRA
`(N=54)
`60.4%*
`
`
`Percentage of responders
`
`*statistically significant versus placebo
`
`
`
`
`Page 10 of 34
`
`
`Page 00010
`
`

`
`Effectiveness For Primary Generalized Tonic-Clonic Seizures In Patients ≥6 Years
`Of Age
`The effectiveness of KEPPRA 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, 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 prosp ective
`ba seline period) were randomized to either KEPPRA or placebo. The 8-week combined baseline
`p riod is referred to as “baseline” in the remaind er of this section.
`e
`The population included 164
`
`patients (KEPPRA N=80, placebo N=84) with idiopathic generalized epilepsy (predominately
`
`juvenile myoclonic epilepsy, juvenile absence ep ilepsy, childhood absence epilepsy, or epilepsy
`
`with Grand Mal seizures on awakening) experiencing primary generalized tonic-clonic seizures.
`
`Each of these syndromes of idiopathic g eneralized epilepsy was well represented in this patient
`
`population. 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 effectiveness was the percent reduction from baseline in weekly PG TC
`seizure frequency for KEPPRA and placebo treatment groups over the treatment period (titration
`+ evaluation periods). There was a statistically significant decrease from baseline in PGTC
`
`frequency in the KEPPRA-treated patients compared to the placebo-treated patients.
`
`Table 6: Median Percent Reduction From Baseline In PGTC Seizure Frequency Per Week
`
`
`
`Percent reduction in PGTC seizure
`frequency
`*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 5.
`
`
`Figure 5: Responder Rate (≥50% Reduction From Baseline) In PGTC Seizure Frequency Per
`Week
`
`
`Placebo
`(N=84)
`44.6%
`
`KEPPRA
`(N=78)
`
`77.6%*
`
`
`
`Page 11 of 34
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`

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`72.2%
`
`*
`
`45.2%
`
`100%
`
`90%
`
`80%
`
`70%
`
`60%
`
`50%
`
`40%
`
`30%
`
`20%
`
`10%
`
`0%
`
`% of Patie
`n
`ts
`
`
`
`Placebo (N=84)
`
`KEPPRA (N=79)
`
`*statistically significant versus placeb o
`
`
`
`INDICATIONS AND USAGE
`
`KEPPRA is indicated as adjunctive therapy in the treatment of partial onset seizures in adults
`
`and children 4 years of age and older with epilepsy.
`
`
`KEPPRA 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.
`
`KEPPRA 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.
`
`CONTRAINDICATIONS
`
`This product should not be administered to patients who have previously exhibited
`hypersensitivity to levetiracetam or any of the inactive ingredients in KEPPRA tablets or oral
`solution.
`
`
`WARNINGS
`
`Suicidal Behavior and Ideation
`
`Antiepileptic drugs (AEDs), including KEPPRA, increase th e risk of suicidal thoughts or
`behavior in patients taking these drugs for any indication. Patients treated with any AED for any
`indication should be monitored for the emergence or worsening of depression, suicidal thoughts
`
`or behavior, and/or any unusual changes in mood or behavior.
`
`Pooled analyses of 199 placebo-controlled clini cal trials (mono- an d adjunctive therapy) of 11
`different AEDs showed that patients randomized to one of the AEDs had approximately twice
`
`
`
`
`Page 12 of 34
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`the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suici dal thinking or behavior compared
`
`to patients randomized to placebo. In these trials, w hich had a median t reatment duration of 12
`
`weeks, the estimated incidence rate of suicidal beha vior or ideation amo ng 27,863 AED-treated
`
`patients w as 0.43%, compared to 0.24% among 16,0 29 placebo-treated patients, rep resenting an
`
`
`increase of approximately one case of suicidal thinking or behavior for every 530 patients
`
`
`treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
`
`patients, but the number is too small to allow any conclusion about drug effect on suicide.
`
`
`The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
`week after starting drug treatment with AEDs and persisted for the duration of treatment
`assessed. Because most trials included in th e analysis did not extend beyond 24 weeks, the risk
`
`of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
`
`The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
`analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
`range of indications suggests that the risk applies to all AEDs used for any indication. The risk
`did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 7 shows
`absolute and relative risk by indication for all evaluated AEDs.
`
`
`
`
`
`Page 13 of 34
`
`
`
`
`Table 7
`Indication
`
`Risk by indication for antiepileptic drugs in the pooled analysis
`Placebo Patients Drug Patients
`Relative Risk:
`Risk Difference:
`with Events Per with Events Per
`Incidence of Events Additional Drug
`1000 Patients
`1000 Pa tients
`in Drug
`Patients with
`Patients/Incidence
`Events Per 1000
`in Placebo Patients
`Patients
`3.5
`2.4
`3.4
`1.0
`Epilepsy
`1.5
`2.9
`8.5
`Psychiatric 5.7
`1.9
`0.9
`1.8
`Other
`1.0
`1.8
`1.9
`4.3
`Total
`2.4
`The relative risk for suicidal thoughts or behavior was higher in clinical trials for epile psy than in
`clinical trials for psychiatric or other conditions, but the absolute risk differences were sim ilar for
`the epilepsy and psychiatric indications.
`
`Anyone considering prescribing KEPPRA or any other AED must balance the risk of suicidal
`thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for
`which AEDs are prescribed are themselves associated with morbidity and mortality and an
`increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
`during treatment, the prescriber needs to consider whether the emergence of these symptoms in
`any given patient may be related to the illness being treated.
`
`Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
`thoughts and behavior and should be advised of the need to be alert for the emergence or
`worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
`
`Page 00013
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`
`
`
` or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
`concern should be reported immediately to healthcare providers.
`
`
`Neuropsychiatric Adverse Events
`
`Partial Onset Seizures
`
`Adults
`In adults experiencing partial onset seizures, KEPPRA use is associated with the occurrence of
`
`
`central nervous syst em adverse events that can be classified into the following categories: 1)
`somnolence and fatigue, 2) coordination difficulties, and 3) behavioral abnormalities.
`
`In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of
`KEPPRA-treated patients reported somnolence, compared to 8.4% of placebo patients. There
`was no clear dose response up to 3000 mg/day. In a study where there was no titration, about
`45% of patients receiving 4000 mg/day reported somnolence. The somnolence was considered
`ser