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LEVETIRACETAM - levetiracetam tablet, film coated
Solco Healthecare US, LLC
DESCRIPTION
Levetiracetam is an antiepileptic drug available as 250 mg (pink), 500 mg (pink), 750 mg (pink), and 1000 mg (white) 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 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/100mL). 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 mLsolvent.)Levetiracetam tablets contain the labeled amount of Levetiracetam. Inactive ingredients: colloidal silicon dioxide, corn starch,magnesium stearate, povidone, talc, and additional agents listed below: 250 mg, 500 Opadry II Pink 40L94198, which contains D and C Red No. 21; FD and C Blue mg, and 750 No. 2; FD and C Red No. 40; FD and C Yellow No. 6; hypromellose 2910 3cP,mg tablets: 6cP, and 50cP; polydextrose FCC; polyethylene glycol 800; titanium dioxide; and triacetin.
1000 mg Opadry II white Y-22-7719, which contains hypromellose 2910 3cP, 6cP,tablets: and 50cP; polydextrose FCC; polyethylene glycol 800; titanium dioxide; and triacetin.
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 benzodiazepines, GABA (gamma-aminobutyric acid), glycine, NMDA (N-methyl-D-aspartate), re-uptake sites, and
second messenger systems. Furthermore, in vitro studies have failed to find an effect of Levetiracetam on neuronal voltage-gated
sodium or T-type calcium currents and levetiracetam does not appear to directly facilitate GABAergic neurotransmission. However, in
vitro studies have demonstrated that Levetiracetam opposes the activity of negative modulators of GABA- and glycine-gated currents
and partially inhibits N-type calcium currents in neuronal cells.
A saturable and stereoselective neuronal binding site in rat brain tissue has been described for Levetiracetam. Experimental data
indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis.
Although the molecular significance of Levetiracetam binding to synaptic vesicle protein SV2A is not understood, levetiracetam
and related analogs showed a rank order of affinity for SV2A which correlated with the potency of their antiseizure activity in
audiogenic seizure-prone mice. These findings suggest that the interaction of Levetiracetam with the SV2A protein may contribute to
the antiepileptic mechanism of action of the drug.
Pharmacokinetics
The pharmacokinetics of Levetiracetam have been studied in healthy adult subjects, adults and pediatric patients with epilepsy, elderlysubjects and subjects with renal and hepatic impairment.
OverviewLevetiracetam is rapidly and almost completely absorbed after oral administration. Levetiracetam tablets and oral solution arebioequivalent. The pharmacokinetics are linear and time-invariant, with low intra- and inter-subject variability. The extent ofbioavailability of Levetiracetam is not affected by food. Levetiracetam is not significantly protein-bound (less than 10% bound) andits volume of distribution is close to the volume of intracellular and extracellular water. Sixty-six percent (66%) of the dose is renallyexcreted 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. Plasmahalf-life of Levetiracetam across studies is approximately 6 to 8 hours. It is increased in the elderly (primarily due to impaired renalclearance) and in subjects with renal impairment.
Absorption and DistributionAbsorption of Levetiracetam is rapid, with peak plasma concentrations occurring in about an hour following oral administration infasted subjects. The oral bioavailability of Levetiracetam tablets is 100% and the tablets and oral solution are bioequivalent in rate andextent of absorption. Food does not affect the extent of absorption of Levetiracetam but it decreases Cmax by 20% and delays Tmaxby 1.5 hours. The pharmacokinetics of Levetiracetam are linear over the dose range of 500 to 5000 mg. Steady-state is achieved after2 days of multiple twice daily dosing. Levetiracetam and its major metabolite are less than 10% bound to plasma proteins; clinicallysignificant interactions with other drugs through competition for protein binding sites are therefore unlikely.
MetabolismLevetiracetam is not extensively metabolized in humans. The major metabolic pathway is the enzymatic hydrolysis of the acetamidegroup, which produces the carboxylic acid metabolite, ucb L 057 (24% of dose) and is not dependent on any liver cytochrome P450isoenzymes. The major metabolite is inactive in animal seizure models. Two minor metabolites were identified as the product ofhydroxylation of the 2-oxo-pyrrolidine ring (2% of dose) and opening of the 2-oxo-pyrrolidine ring in position 5 (1% of dose). Thereis no enantiomeric interconversion of Levetiracetam or its major metabolite.
EliminationLevetiracetam plasma half-life in adults is 7 ± 1 hour and is unaffected by either dose or repeated administration. Levetiracetam iseliminated from the systemic circulation by renal excretion as unchanged drug which represents 66% of administered dose. The totalbody clearance is 0.96 mL/min/kg and the renal clearance is 0.6 mL/min/kg. The mechanism of excretion is glomerular filtration withsubsequent partial tubular reabsorption. The metabolite ucb L 057 is excreted by glomerular filtration and active tubular secretion witha renal clearance of 4 mL/min/kg. Levetiracetam elimination is correlated to creatinine clearance. Levetiracetam clearance is reducedin patients with impaired renal function (see Special Populations, Renal Impairment and DOSAGE AND ADMINISTRATION,Adult Patients with Impaired Renal Function).
Pharmacokinetic InteractionsIn vitro data on metabolic interactions indicate that Levetiracetam is unlikely to produce, or be subject to, pharmacokineticinteractions. Levetiracetam and its major metabolite, at concentrations well above Cmax levels achieved within the therapeutic doserange, 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 clinicalstudies in epilepsy patients (see PRECAUTIONS, Drug Interactions).
Special PopulationsElderlyPharmacokinetics of Levetiracetam were evaluated in 16 elderly subjects (age 61 to 88 years) with creatinine clearance ranging from30 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 thesesubjects.
Pediatric PatientsPharmacokinetics of Levetiracetam were evaluated in 24 pediatric patients (age 6 to12 years) after single dose (20 mg/kg). The bodyweight adjusted apparent clearance of Levetiracetam was approximately 40% higher than in adults.
A repeat dose pharmacokinetic study was conducted in pediatric patients (age 4 to 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 L 057 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 (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. 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 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 to 80 mL/min), 50% in the
moderate group (CLcr = 30 to 50 mL/min) and 60% in the severe renal impairment group (CLcr less than 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 greater
than 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 ADMINISTRATION, 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 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.
CLINICAL STUDIES
In the following studies, statistical significance versus placebo indicates a p value less than 0.05.
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, placebocontrolled 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 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 greater than or equal to 50%
reduction from baseline in partial onset seizure frequency). The results of the analysis of Study 1 are displayed in Table 1.
Table 1: Reduction In Mean Over Placebo In Weekly Frequency Of Partial Onset Seizures In Study 1
Percent reduction in partial seizure frequency * Statistically significant versus placeboThe percentage of patients (y-axis) who achieved greater than or equal to 50% reduction in weekly seizure rates from baseline inpartial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatmentgroups (x-axis) is presented in Figure 1.
Figure 1: Responder Rate (greater than or equal to 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 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 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 greater than or equal to 50% reduction from baseline 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 Partial Onset Seizures In Study 2: Period A
Percent reduction in frequency overplacebo * statistically significant versus placeboThe percentage of patients (y-axis) who achieved greater than or equal to 50% reduction in weekly seizure rates from baseline inpartial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatmentgroups (x-axis) is presented in Figure 2.
Figure 2: Responder Rate (greater than or equal to 50% Reduction From Baseline) In Study 2: Period A

* statistically significant versus placebo
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 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 greater than or equal to 50% reduction from baseline in partial 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
Percent reduction in partial seizure frequency over placebo *Statistically significant versus placeboThe percentage of patients (y-axis) who achieved greater than or equal to 50% reduction in weekly seizure rates from baseline inpartial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatmentgroups (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 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, 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 to 2 AEDs,
who still experienced at least 4 partial onset seizures during the 4 weeks prior to screening, as well as at least 4 partial onset seizures
in each of the two 4 week baseline periods, were randomized to receive either 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 greater than or equal to 50% reduction from baseline in partial 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 placeboThe percentage of patients (y-axis) who achieved greater than or equal to 50% reduction in weekly seizure rates from baseline inpartial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatmentgroups (x-axis) is presented in Figure 4.
Figure 4: Responder Rate (greater than or equal to 50% Reduction From Baseline)

* statistically significant versus placebo
Effectiveness In 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, doubleblind,
placebo-controlled study, 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 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 (greater than or equal to 50% Reduction From Baseline) In Myoclonic Seizure Days Per Week for Patients
with JME
*statistically significant versus placebo
Effectiveness For 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, 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. 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. 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 PGTC seizure frequency for Levetiracetam
and placebo treatment groups over the treatment period (titration + evaluation periods). There was a statistically significant decrease

from baseline in PGTC frequency in the Levetiracetam-treated patients compared to the placebo-treated patients. Table 6: MedianPercent Reduction From Baseline In PGTC Seizure Frequency Per Week.
Table 6: Median Percent Reduction From Baseline In PGTC Seizure Frequency Per Week Percent reduction in PGTC seizure *statistically significant versus placeboThe percentage of patients (y-axis) who achieved greater than or equal to 50% reduction in weekly seizure rates from baseline inPGTC 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 (greater than or equal to 50% Reduction From Baseline) In PGTC Seizure Frequency Per week *statistically significant versus placebo INDICATIONS AND USAGE
Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and
older with 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 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 levetiracetam tablets.
WARNINGS
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs) including Levetiracetam, increases the 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 clinical trials (mono and adjunctive therapy) of 11 different AEDs showed that patients
randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking
or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the
estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among
16,029 placebo-treated patients, representing 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 withAEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24weeks, 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 riskwith AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used forany indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 7 shows absolute andrelative risk by indication for all evaluated AEDs.
Table 7: Risk by indication for antiepileptic drugs in the pooled Analysis Patients/ Incidence in Placebo Patients The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other
conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing Levetiracetam 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,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, Levetiracetam use is associated with the occurrence of central nervous system 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 Levetiracetam-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 serious in 0.3% of
the 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 patients. In 1.4% of treated patients and in 0.9% of placebo patients the dose was reduced,
while 0.3% of the treated patients were hospitalized due to somnolence.
In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of treated patients reported asthenia,
compared to 9.1% of placebo patients. Treatment was discontinued in 0.8% of treated patients as compared to 0.5% of placebo
patients. In 0.5% of treated patients and in 0.2% of placebo patients the dose was reduced.
A total of 3.4% of Levetiracetam-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or
in coordination) compared to 1.6% of placebo patients. A total of 0.4% of patients in controlled trials discontinued Levetiracetam
treatment due to ataxia, compared to 0% of placebo patients. In 0.7% of treated patients and in 0.2% of placebo patients the dose was
reduced due to coordination difficulties, while one of the treated patients was hospitalized due to worsening of pre-existing ataxia.
Somnolence, asthenia and coordination difficulties occurred most frequently within the first 4 weeks of treatment.
In controlled trials of patients with epilepsy experiencing partial onset seizures, 5 (0.7%) of Levetiracetam-treated patients
experienced psychotic symptoms compared to 1 (0.2%) placebo patient. Two (0.3%) Levetiracetam-treated patients were hospitalized
and their treatment was discontinued. Both events, reported as psychosis, developed within the first week of treatment and resolved
within 1 to 2 weeks following treatment discontinuation. Two other events, reported as hallucinations, occurred after 1 to 5 months
and resolved within 2 to 7 days while the patients remained on treatment. In one patient experiencing psychotic depression occurring
within a month, symptoms resolved within 45 days while the patient continued treatment. A total of 13.3% of Levetiracetam patients
experienced other behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression,
emotional lability, hostility, irritability, etc.) compared to 6.2% of placebo patients. Approximately half of these patients reported
these events within the first 4 weeks. A total of 1.7% of treated patients discontinued treatment due to these events, compared to 0.2%
of placebo patients. The treatment dose was reduced in 0.8% of treated patients and in 0.5% of placebo patients. A total of 0.8% of
treated patients had a serious behavioral event (compared to 0.2% of placebo patients) and were hospitalized.
Pediatric Patients
In pediatric patients experiencing partial onset seizures, Levetiracetam is associated with somnolence, fatigue, and behavioral
abnormalities.
In the double-blind, controlled trial in children with epilepsy experiencing partial onset seizures, 22.8% of Levetiracetam-treated
patients experienced somnolence, compared to 11.3% of placebo patients. The design of the study prevented accurately assessing
doseresponse effects. No patient discontinued treatment for somnolence. In about 3.0% of Levetiracetam-treated patients and in 3.1%
of placebo patients the dose was reduced as a result of somnolence.
Asthenia was reported in 8.9% of Levetiracetam-treated patients, compared to 3.1% of placebo patients. No patient discontinued
treatment for asthenia, but asthenia led to a dose reduction in 3.0% of Levetiracetam-treated patients compared to 0% of placebo
patients.
A total of 37.6% of the Levetiracetam-treated patients experienced behavioral symptoms (reported as agitation, anxiety, apathy,
depersonalization, depression, emotional lability, hostility, hyperkinesia, nervousness, neurosis, and personality disorder), compared
to 18.6% of placebo patients. Hostility was reported in 11.9% of Levetiracetam-treated patients, compared to 6.2% of placebo patients.
Nervousness was reported in 9.9% of Levetiracetam-treated patients, compared to 2.1% of placebo patients. Depression was reported
in 3.0% of Levetiracetam-treated patients, compared to 1.0% of placebo patients.
A total of 3.0% of Levetiracetam-treated patients discontinued treatment due to psychotic and nonpsychotic adverse events, compared
to 4.1% of placebo patients. Overall, 10.9% of Levetiracetam-treated patients experienced behavioral symptoms associated with
discontinuation or dose reduction, compared to 6.2% of placebo patients.
Myoclonic Seizures
During clinical development, the number of patients with myoclonic seizures exposed to Levetiracetam was considerably smaller
than the number with partial seizures. Therefore, under-reporting of certain adverse events was more likely to occur in the myoclonic
seizure population. In adult and adolescent patients experiencing myoclonic seizures, Levetiracetam is associated with somnolence
and behavioral abnormalities. It is expected that the events seen in partial seizure patients would occur in patients with JME.
In the double-blind, controlled trial in adults and adolescents with juvenile myoclonic epilepsy experiencing myoclonic seizures,
11.7% of Levetiracetam -treated patients experienced somnolence compared to 1.7% of placebo patients. No patient discontinued
treatment as a result of somnolence. In 1.7% of Levetiracetam -treated patients and in 0% of placebo patients the dose was reduced as
a result of somnolence.
Non-psychotic behavioral disorders (reported as aggression and irritability) occurred in 5% of the Levetiracetam -treated patients
compared to 0% of placebo patients. Nonpsychotic mood disorders (reported as depressed mood, depression, and mood swings)
occurred in 6.7% of Levetiracetam -treated patients compared to 3.3% of placebo patients. A total of 5.0% of Levetiracetam -treated
patients had a reduction in dose or discontinued treatment due to behavioral or psychiatric events (reported as anxiety, depressed
mood, depression, irritability, and nervousness), compared to 1.7% of placebo patients.
Primary Generalized Tonic-Clonic Seizures:
During clinical development, the number of patients with primary generalized tonic-clonic epilepsy exposed to Levetiracetam was
considerably smaller than the number with partial epilepsy, described above. As in the partial seizure patients, behavioral symptoms
appeared to be associated with Levetiracetam treatment. Gait disorders and somnolence were also described in the study in primary
generalized seizures, but with no difference between placebo and Levetiracetam treatment groups and no appreciable discontinuations.
Although it may be expected that drug related events seen in partial seizure patients would be seen in primary generalized epilepsy
patients (e.g. somnolence and gait disturbance), these events may not have been observed because of the smaller sample size.
In patients 6 years of age and older experiencing primary generalized tonic-clonic seizures, Levetiracetam is associated with
behavioral abnormalities.
In the double-blind, controlled trial in patients with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic
seizures, irritability was the most frequently reported psychiatric adverse event occurring in 6.3% of Levetiracetam-treated patients
compared to 2.4% of placebo patients. Additionally, nonpsychotic behavioral disorders (reported as abnormal behavior, aggression,
conduct disorder, and irritability) occurred in 11.4% of the Levetiracetam-treated patients compared to 3.6% of placebo patients.
Of the Levetiracetam-treated patients experiencing non-psychotic behavioral disorders, one patient discontinued treatment due
to aggression. Non-psychotic mood disorders (including anger, apathy, depression, mood altered, mood swings, negativism, and
tearfulness) occurred in 12.7% of Levetiracetam-treated patients compared to 8.3% of placebo patients. No Levetiracetam-treated
patients discontinued or had a dose reduction as a result of these events. One patient experienced delusional behavior that required the
lowering of the dose of Levetiracetam.
In a long-term open label study that examined patients with various forms of primary generalized epilepsy, along with the
nonpsychotic behavioral disorders, 2 of 192 patients studied exhibited psychotic-like behavior. Behavior in one case was characterized
by auditory hallucinations and suicidal thoughts and led to Levetiracetam discontinuation. The other case was described as worsening
of preexistent schizophrenia and did not lead to drug discontinuation.
Withdrawal Seizures
Antiepileptic drugs, including Levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency.
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 significant (less than or equal to 2.8 x 109/L)decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (less than or equal to 1.0 x 109/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.
Pediatric Patients
Minor, but 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 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.
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.
Information For Patients
Patients and caregivers should be informed of the availability of a Medication Guide, and they should be instructed to read the
Medication Guide prior to taking Levetiracetam. Patients should be instructed to take Levetiracetam only as prescribed.
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 immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician as
suicide, suicide attempt and suicidal ideation have been reported in patients treated with Levetiracetam.
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.
This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free
number 1-888-233-2334. (See Pregnancy Section).
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.
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.
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.
Levetiracetam circulates largely unbound (less than 10% bound) to plasma proteins; clinically significant interactions with other drugs
through competition for protein binding sites are therefore unlikely.
Potential pharmacokinetic interactions were assessed in clinical pharmacokinetic studies (phenytoin, valproate, oral contraceptive,
digoxin, warfarin, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients.
Drug-Drug Interactions Between Levetiracetam And Other Antiepileptic Drugs (AEDs)
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.
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.
Other Drug Interactions
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. Co-administration 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. Co-administration 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. Co-administration 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. 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.
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 systemicexposure (AUC) approximately 6 times that achieved in humans receiving the MRHD. There was no evidence of carcinogenicity. Astudy 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 potentialfor a carcinogenic response has not been fully evaluated in that species because adequate doses have not been studied.
MutagenesisLevetiracetam 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 vivomouse micronucleus assay. The hydrolysis product and major human metabolite of Levetiracetam ucb L057 was not mutagenic in theAmes test or the in vitro mouse lymphoma assay.
Impairment Of FertilityNo 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).
Pregnancy
Pregnancy Category C
In animal studies, Levetiracetam produced evidence of developmental toxicity at doses similar to or greater than human therapeutic
doses.
Administration to female rats throughout pregnancy and lactation was associated with increased incidences of minor fetal skeletal
abnormalities and retarded offspring growth pre- and/or postnatally at doses greater than or equal to 350 mg/kg/day (approximately
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.
Treatment of pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and increased incidences of minor fetal skeletal abnormalities at doses greater than or equal to 600 mg/kg/day (approximately 4 times MRHD on a mg/m2basis) 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 (1.3 times the MRHD on a mg/m2 basis). Maternaltoxicity was also observed at 1800 mg/kg/day.
When pregnant rats were treated during the period of organogenesis, fetal weights were decreased and the incidence of fetalskeletal variations was increased at a dose of 3600 mg/kg/day (12 times the MRHD). 1200 mg/kg/day (4 times the MRHD) was adevelopmental 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).
There are no adequate and well-controlled studies in pregnant women. Levetiracetam should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus. As with other antiepileptic drugs, physiological changes during pregnancy
may affect Levetiracetam concentration. There have been reports of decreased Levetiracetam concentration during pregnancy.
Discontinuation of antiepileptic treatments may result in disease worsening, which can be harmful to the mother and the fetus.
Pregnancy Registries
To provide information regarding the effects of in utero exposure to Levetiracetam, physicians are advised to recommend that
pregnant patients taking Levetiracetam enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry. This can be
done by calling the toll free number 1-888-233-2334, and must be done by the patients themselves. Information on the registry can
also be found at the website http://www.aedpregnancyregistry.org/.
To ensure broad program access and reach, either a healthcare provider or the patient can initiate enrollment in the North American
Antiepileptic Drug Pregnancy Registry by calling (888) 233-2334 (toll free).
Labor And Delivery
The effect of Levetiracetam on labor and delivery in humans is unknown.
Nursing Mothers
Levetiracetam is excreted in breast 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.
Pediatric Use
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 dose of 60 mg/kg/day on a mg/m2 basis) did not
indicate a potential for age-specific toxicity.
Geriatric Use
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.
A study in 16 elderly subjects (age 61 to 88 years) with oral administration of single dose and multiple twice daily doses for 10 days
showed no pharmacokinetic differences related to age alone.
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.
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 (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION, Adult Patients with Impaired Renal
Function).
ADVERSE REACTIONS
The prescriber should be aware that the adverse event incidence figures in the following tables, obtained when Levetiracetam was
added to concurrent AED therapy, cannot be used to predict the frequency of adverse experiences in the course of usual medical
practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited
frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses,
or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative
contribution of drug and non-drug factors to the adverse event incidences in the population studied.
Partial Onset Seizures
In well-controlled clinical studies in adults with partial onset seizures, the most frequently reported adverse events associated withthe use of Levetiracetam in combination with other AEDs, not seen at an equivalent frequency among placebotreated patients, weresomnolence, asthenia, infection and dizziness. In the well-controlled pediatric clinical study in children 4 to 16 years of age withpartial onset seizures, the adverse events most frequently reported with the use of Levetiracetam in combination with other AEDs,not seen at an equivalent frequency among placebotreated patients, were somnolence, accidental injury, hostility, nervousness, andasthenia.
Table 8 lists treatment-emergent adverse events that occurred in at least 1% of adult epilepsy patients treated with Levetiracetamparticipating in placebo-controlled studies and were numerically more common than in patients treated with placebo. Table 9lists treatment-emergent adverse events that occurred in at least 2% of pediatric epilepsy patients (ages 4 to 16 years) treated withLevetiracetam participating in the placebo-controlled study and were numerically more common than in pediatric patients treated withplacebo. In these studies, either Levetiracetam or placebo was added to concurrent AED therapy. Adverse events were usually mild tomoderate in intensity.
Table 8: Incidence (%) Of Treatment-Emergent Adverse Events In Placebo-Controlled,Add-On Studies In Adults Experiencing Partial Onset Seizures By Body System(Adverse Events Occurred In At Least 1% Of Levetiracetam-Treated Patients AndOccurred More Frequently Than Placebo-Treated Patients) Body System/
Adverse Event
Body as a Whole
Digestive System
Nervous System
Emotional Lability Respiratory System
Special Senses
Other events reported by at least 1% of adult Levetiracetam-treated patients but as or more frequent in the placebo group werethe following: abdominal pain, accidental injury, amblyopia, arthralgia, back pain, bronchitis, chest pain, confusion, constipation,convulsion, diarrhea, drug level increased, dyspepsia, ecchymosis, fever, flu syndrome, fungal infection, gastroenteritis, gingivitis,grand mal convulsion, insomnia, nausea, otitis media, rash, thinking abnormal, tremor, urinary tract infection, vomiting and weightgain.
Table 9: Incidence (%) Of Treatment-Emergent Adverse Events In A Placebo-Controlled,Add-On Study In Pediatric Patients Ages 4 to 16 Years Experiencing Partial OnsetSeizures By Body System (Adverse Events Occurred In At Least 2% Of Levetiracetam-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients) Body System/
Adverse Event
Body as a Whole
Accidental Injury Digestive System
Hemic and Lymphatic System
Metabolic and Nutritional
Nervous System
Personality Disorder Emotional Lability Reflexes Increased Respiratory System
Skin and Appendages
Skin Discoloration Vesiculobullous Rash Special Senses
Urogenital System
Urine Abnormality Other events occurring in at least 2% of pediatric Levetiracetam-treated patients but as or more frequent in the placebo group were the
following: abdominal pain, allergic reaction, ataxia, convulsion, epistaxis, fever, headache, hyperkinesia, infection, insomnia, nausea,
otitis media, rash, sinusitis, status epilepticus (not otherwise specified), thinking abnormal, tremor, and urinary incontinence.
Myoclonic Seizures
Although the pattern of adverse events 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 event pattern for
patients with JME is expected to be essentially the same as for patients with partial seizures.
In the well-controlled clinical study that included both adolescent (12 to 16 years of age) and adult patients with myoclonic seizures,
the most frequently reported adverse events associated with the use of Levetiracetam in combination with other AEDs, not seen at an
equivalent frequency among placebo-treated patients, were somnolence, neck pain, and pharyngitis.
Table 10 lists treatment-emergent adverse events 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. Adverse events were usually mild to moderate in
intensity.
Table 10: Incidence (%) Of Treatment-Emergent Adverse Events In A Placebo-Controlled,
Add-On Study In Patients 12 Years Of Age And Older With Myoclonic Seizures By
Body System (Adverse Events Occurred In At Least 5% Of Levetiracetam -Treated
Patients And Occurred More Frequently Than Placebo-Treated Patients)
Body System/
MedDRA preferred term
Ear and labyrinth disorders
Infections and infestations
Musculoskeletal and connective tissue
disorders
Nervous system disorders
Psychiatric disorders
Other events occurring in at least 5% of Levetiracetam treated patients with myoclonic seizures but as or more frequent in the placebo
group were the following: fatigue and headache.
Primary Generalized Tonic-Clonic Seizures
Although the pattern of adverse events 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 event pattern for
patients with PGTC seizures is expected to be essentially the same as for patients with partial seizures.
In the well-controlled clinical study that included patients 4 years of age and older with primary generalized tonic-clonic (PGTC)
seizures, the most frequently reported adverse event associated with the use of Levetiracetam in combination with other AEDs, not
seen at an equivalent frequency among placebo-treated patients, was nasopharyngitis.
Table 11 lists treatment-emergent adverse events 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. Adverse events were usually mild to moderate in intensity.
Table 11: Incidence (%) Of Treatment-Emergent Adverse Events In A Placebo-Controlled,
Add-On Study In Patients 4 Years Of Age And Older With PGTC Seizures By MedDRA
System Organ Class (Adverse Events Occurred In At Least 5% Of Levetiracetam-TreatedPatients And Occurred More Frequently Than Placebo-Treated Patients) MedDRA System Organ Class/
Preferred Term
Gastrointestinal disorders
General disorders and administration
Infections and infestations
Psychiatric disorders
Other events occurring in at least 5% of Levetiracetam-treated patients with PGTC seizures but as or more frequent in the placebo
group were the following: dizziness, headache, influenza, and somnolence.
Time Course Of Onset Of Adverse Events For Partial Onset Seizures
Of the most frequently reported adverse events in adults experiencing partial onset seizures, asthenia, somnolence and dizziness
appeared to occur predominantly during the first 4 weeks of treatment with Levetiracetam.
Discontinuation Or Dose Reduction In Well-Controlled Clinical Studies
Partial Onset Seizures
In well-controlled adult clinical studies, 15.0% of patients receiving Levetiracetam and 11.6% receiving placebo either discontinued or
had a dose reduction as a result of an adverse event. Table 12 lists the most common (greater than 1%) adverse events that resulted in
discontinuation or dose reduction.
Table 12: Adverse Events That Most Commonly Resulted In Discontinuation Or Dose
Reduction In Placebo-Controlled Studies In Adult Patients Experiencing Partial Onset
Seizures
In the well-controlled pediatric clinical study, 16.8% of patients receiving Levetiracetam and 20.6% receiving placebo eitherdiscontinued or had a dose reduction as a result of an adverse event. The adverse events most commonly associated (greater than orequal to 3% in patients receiving Levetiracetam) with discontinuation or dose reduction in the well-controlled study are presented inTable 13.
Table 13: Adverse Events Most Commonly Associated With Discontinuation Or Dose Reduction In The Placebo-Controlled Study In Pediatric Patients Ages 4 to 16 YearsExperiencing Partial Onset Seizures Myoclonic Seizures
In the placebo-controlled study, 8.3% of patients receiving Levetiracetam and 1.7% receiving placebo either discontinued or had a
dose reduction as a result of an adverse event. The adverse events that led to discontinuation or dose reduction in the well-controlled
study are presented in Table 14.
Table 14: Adverse Events That Resulted In Discontinuation Or Dose Reduction In The
Placebo-Controlled Study In Patients With Juvenile Myoclonic Epilepsy
Body System/
Primary Generalized Tonic-Clonic Seizures
In the placebo-controlled study, 5.1% of patients receiving Levetiracetam and 8.3% receiving placebo either discontinued or had a
dose reduction during the treatment period as a result of a treatment-emergent adverse event.
This study was too small to adequately characterize the adverse events leading to discontinuation. It is expected that the adverse
events that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy
trials (see tables 12 - 14).
Comparison Of Gender, Age And Race
The overall adverse experience profile of Levetiracetam was similar between females and males. There are insufficient data to support
a statement regarding the distribution of adverse experience reports by age and race.
Postmarketing Experience
In addition to the adverse experiences listed above, the following have been reported in patients receiving marketed Levetiracetam
worldwide. The listing is alphabetized: abnormal liver function test, hepatic failure, hepatitis, leukopenia, neutropenia, pancreatitis,
pancytopenia (with bone marrow suppression identified in some of these cases), thrombocytopenia, and weight loss. Alopecia has
been reported with Levetiracetam use; recovery was observed in the majority of cases where Levetiracetam was discontinued. These
adverse experiences have not been listed above, and data are insufficient to support an estimate of their incidence or to establishcausation.
DRUG ABUSE AND DEPENDENCE
The abuse and dependence potential of Levetiracetam has not been evaluated in human studies.
OVERDOSAGE
Signs, Symptoms And Laboratory Findings Of Acute Overdosage In Humans
The highest known dose of Levetiracetam received in the clinical development program was 6000 mg/day. Other than drowsiness,
there were no adverse events 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.
Treatment Or 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.
DOSAGE AND ADMINISTRATION
Levetiracetam is indicated as adjunctive treatment of partial onset seizures in adults and children 4 years of age and older with
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 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.
Partial Onset Seizures
Adults 16 Years And Older
In clinical trials, daily doses of 1000 mg, 2000 mg, and 3000 mg, given as twice daily dosing, were shown to be effective. Although
in some studies there was a tendency toward greater response with higher dose (see CLINICAL STUDIES), a consistent increase in
response with increased dose has not been shown.
Treatment should be initiated with a daily dose of 1000 mg/day, given as twice daily dosing (500 mg BID). Additional dosing
increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg. Doses greater
than 3000 mg/day have been used in open-label studies for periods of 6 months and longer. There is no evidence that doses greater
than 3000 mg/day confer additional benefit.
Pediatric Patients Ages 4 To less than 16 Years
Treatment should be initiated with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg BID). The daily dose should be increased
every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg BID). 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 52 mg/kg. Patients with body
weight less than or equal to 20 kg should be dosed with oral solution. Patients with body weight above 20 kg can be dosed with either
tablets or oral solution. Table 15 below provides a guideline for tablet dosing based on weight during titration to 60 mg/kg/day. Only
whole tablets should be administered.
Levetiracetam is given orally with or without food.
Table 15: Levetiracetam Tablet Weight-Based Dosing Guide For Children
Patient Weight
Daily Dose
Daily Dose
Daily Dose
20 mg/kg/day
40 mg/kg/day
60 mg/kg/day
(BID dosing)
(BID dosing)
(BID dosing)
20.1 to 40 kg
greater than 40 kg
The following calculation should be used to determine the appropriate daily dose of oral solution for pediatric patients based on a
daily dose of 20 mg/kg/day, 40 mg/kg/day or 60 mg/kg/day:
Total daily dose (mL/day) = Daily dose (mg/kg/day) x patient weight (kg)
100 mg/mL
A household teaspoon or tablespoon is not an adequate measuring device. It is recommended that a calibrated measuring device be
obtained and used. Healthcare providers should recommend a device that can measure and deliver the prescribed dose accurately, and
provide instructions for measuring the dosage.
Myoclonic Seizures In Patients 12 Years Of Age And Older With Juvenile Myoclonic Epilepsy
Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg BID). Dosage should be increased 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.
Primary Generalized Tonic-Clonic Seizures
Adults 16 Years And Older
Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg BID). Dosage should be increased 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 less than 16 Years
Treatment should be initiated with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg BID). The daily dose should be increased
every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg BID). The effectiveness of doses
lower than 60 mg/kg/day has not been adequately studied. Patients with body weight less than or equal to 20 kg should be dosed with
oral solution. Patients with body weight above 20 kg can be dosed with either tablets or oral solution. See Table 15 for tablet dosing
based on weight during titration to 60 mg/kg/day. Only whole tablets should be administered.
Adult Patients With Impaired Renal Function
Levetiracetam dosing must be individualized according to the patient's renal function status. Recommended doses and adjustment for
dose for adults are shown in Table 16. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in mL/min is
needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the following formula:
CLcr = [140-age (years)] x weight (kg) (x 0.85 for female patients)
72 x serum creatinine (mg/dL)
Table 16: Dosing Adjustment Regimen For Adult Patients With Impaired Renal Function
Creatinine Clearance (mL/min) ESRD patients using dialysis 1 Following dialysis, a 250 to 500 mg supplemental dose is recommended.
HOW SUPPLIED
Levetiracetam tablets, 250 mg are pink, oblong-shaped, bi-convex, scored film coated tablets, debossed "SLC 221" on either side of
the score and plain on the other side. They are supplied in containers of 120 tablets (NDC 43547-221-15).
Levetiracetam tablets, 500 mg are pink, oblong-shaped, bi-convex, scored film coated tablets, debossed "SLC 222" on either side of
the score and plain on the other side. They are supplied in containers of 120 tablets (NDC 43547-222-15), and 1,000 tablets (NDC
43547-222-11).
Levetiracetam tablets, 750 mg are pink, oblong-shaped, bi-convex, scored film coated tablets, debossed "SLC 223" on either side of
the score and plain on the other side. They are supplied in containers of 120 tablets (NDC 43547-223-15).
Levetiracetam tablets, 1000 mg are white to off-white, modified capsules shaped, biconvex, scored film-coated tablets debossed "SLC
224" on either side of the score and plain on the other side. They are supplied in containers of 60 tablets (NDC 43547-224-06).
STORAGE
Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Pharmacist: Dispense in a tight, light-resistant container with a child-resistant closure.
Manufactured by:
Legacy Pharmaceuticals Puerto Rico, LLC
Humacao, Puerto Rico 00791
Distributed by:
Solco Healthcare US, LLC
Humacao, Puerto Rico 00791
Rev. October 2010
MEDICATION GUIDE
Levetiracetam Tablets
250 mg, 500 mg, 750 mg, and 1000 mg
Read the Medication Guide that comes with Levetiracetam tablets before you start using it and each time you get a refill. There may
be new information. This leaflet does not take the place of talking with your healthcare provider about your condition or treatment.
What is the most important information I should know about Levetiracetam?
Like other antiepileptic drugs, Levetiracetam may cause suicidal thoughts or actions in a very small number of people, about 1
in 500 people taking it.
Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood
Do not stop Levetiracetam without first talking to a healthcare provider.
• Stopping Levetiracetam suddenly can cause serious problems. Stopping a seizure medicine suddenly can cause seizures that will not
stop (status epilepticus).
• Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare
provider may check for other causes.
How can I watch for early symptoms of suicidal thoughts and actions?
• Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.
• Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
What is Levetiracetam?
Levetiracetam is a prescription medicine taken by mouth that is used with other medicines to treat:
• partial onset seizures in patients 4 years of age and older with epilepsy
• myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy
• primary generalized tonic-clonic seizures in people 6 years of age and older with certain types of generalized epilepsy.
It is not known if Levetiracetam is safe or effective in children under 4 years of age.
Before taking your medicine, make sure you have received the correct medicine. Compare the name above with the name on your
bottle and the appearance of your medicine with the description of Levetiracetam tablets provided below. Contact your pharmacist
immediately if you believe a dispensing error may have occurred.
250 mg Levetiracetam tablets are pink, oblong-shaped, bi-convex, scored film coated tablets, debossed "SLC 221" on either side of
the score and plain on the other side.
500 mg Levetiracetam tablets are pink, oblong-shaped, bi-convex, scored film coated tablets, debossed "SLC 222" on either side of
the score and plain on the other side.
750 mg Levetiracetam tablets are pink, oblong-shaped, bi-convex, scored film coated tablets, debossed "SLC 223" on either side of
the score and plain on the other side.
1000 mg Levetiracetam tablets are white to off-white, modified capsules shaped, biconvex, scored film-coated tablets debossed "SLC
224" on either side of the score and plain on the other side.
What should I tell my healthcare provider before starting Levetiracetam tablets?
Before starting Levetiracetam, tell your healthcare provider about all of your medical conditions, including if you:
• have or have had depression, mood problems or suicidal thoughts or behavior
• have kidney problem
• are pregnant or planning to become pregnant. It is not known if Levetiracetam will harm your unborn baby. You and your healthcare
provider will have to decide if you should take Levetiracetam while you are pregnant. If you become pregnant
while taking Levetiracetam, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy
Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the
safety of Levetiracetam and other antiepileptic medicine during pregnancy.
• are breast feeding. Levetiracetam can pass into your milk and may harm your baby. You and your healthcare provider should discuss
whether you should take Levetiracetam or breastfeed; you should not do both.
Tell your healthcare provider about all the medicines you take, including prescription, nonprescription medications, vitamins, and
herbal supplements. Do not start a new medicine without first talking with your healthcare provider.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine.
How should I take Levetiracetam tablets?
Take Levetiracetam tablets exactly as prescribed
• Your healthcare provider will tell you how much Levetiracetam to take and when to take it. Levetiracetam is usually taken twice a
day. Take Levetiracetam at the same times each day.
• Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.
• Take Levetiracetam with or without food.
• Swallow the tablets whole. Do not chew or crush tablets. Use the Ask your healthcare provider for Levetiracetam oral solution if you
cannot swallow tablets.
• If your healthcare provider has prescribed Levetiracetam oral solution, be sure to ask your pharmacist for a medicine dropper or
medicine cup to help you measure the correct amount of Levetiracetam oral solution. Do not use a household teaspoon. Ask your
pharmacist for instructions on how to use the measuring device the right way.
• If you miss a dose of Levetiracetam, take it as soon as you remember. If it is almost time for your next dose, just skip the missed
dose. Take the next dose at your regular time. Do not take two doses at the same time.
• If you take too much Levetiracetam, call your local Poison Control Center or go to the nearest emergency room right away.
What should I avoid while taking Levetiracetam tablets?
Do not drive, operate machinery or do other dangerous activities until you know how Levetiracetam tablets affect you. Levetiracetam
tablets may make you dizzy or sleepy.
What are the possible side effects of Levetiracetam tablets?
• See "What is the most important information I should know about Levetiracetam?"
Levetiracetam can cause serious side effects.
Call your healthcare provider right away if you have any of the following symptoms:
• mood and behavior changes such as aggression, agitation, anger, anxiety, apathy, mood swings, depression, hostility, and irritability.
A few people may get psychotic symptoms such as hallucinations (seeing or hearing things that are
really not there), delusions (false or strange thoughts or beliefs) and unusual behavior
• extreme sleepiness, tiredness, and weakness
• problems with muscle coordination (problems walking and moving)
The most common side effects seen in people who take Levetiracetam include:
• sleepiness
• weakness
• dizziness
• infection
The most common side effects with Levetiracetam in children, in addition to those listed above are:
• accidental injury
• irritability
• hostility
These side effects could happen at any time but happen more often within the first 4 weeks of treatment except for infection.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Levetiracetam. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Levetiracetam tablets?
• Store Levetiracetam at room temperature, 59°F to 86°F (15° C to 30°C) away from heat and light.
• Keep Levetiracetam tablets and all medicines out of the reach of children.
General information about Levetiracetam tablets
Medicines are sometimes prescribed for purposes other than those described in patient information leaflets. Do not use Levetiracetam
tablets for a condition for which it was not prescribed. Do not give your Levetiracetam tablets to other people, even if they have the
same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about Levetiracetam tablets. If you would like more information,
talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Levetiracetam tablets
that is written for healthcare professionals. You can also get information about Levetiracetam tablets at www.solcohealthcare.com.
What are the ingredients of Levetiracetam tablets?

Levetiracetam tablets contain the labeled amount of Levetiracetam. Inactive ingredients: colloidal silicon dioxide, corn starch,
magnesium stearate, povidone, talc, and additional agents listed below:
250 mg, 500 Opadry II Pink 40L94198, which contains D and C Red No. 21; FD and C Blue
mg, and 750 No. 2; FD and C Red No. 40; FD and C Yellow No. 6; hypromellose 2910 3cP,
mg tablets: 6cP, and 50cP; polydextrose FCC; polyethylene glycol 800; titanium dioxide; and triacetin.
1000 mg Opadry II white Y-22-7719, which contains hypromellose 2910 3cP, 6cP,
tablets: and 50cP; polydextrose FCC; polyethylene glycol 800; titanium dioxide; and triacetin.
Levetiracetam tablets do not contain lactose or gluten.
Call your doctor for medical advice about side effects. To report SUSPECTED ADVERSE REACTIONS, contact Legacy
Pharmaceuticals Puerto Rico, LLC and www.solcohealthcare.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
Rx Only
This Medication Guide has been approved by the US Food and Drug Administration.
Manufactured by:
Legacy Pharmaceuticals Puerto Rico, LLC
Humacao, Puerto Rico 00791
Distributed by:
Solco Healthcare US, LLC
Humacao, Puerto Rico 00791
Rev. October 2010
Code: 02-3036-EX-01
CONTAINER LABELS
250mg Label
Rx Only
NDC 43547-221-15
Dispense accompanying Medication Guide to each patient.
120 Tablets
Dispense in a tight, light resistant container with a child resistant closure.
Each tablet contains 250 mg of levetiracetam.
See enclosed package insert for dosage information.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see
USP Controlled Room Temperature].
Manufactured by:
Legacy Pharmaceuticals Puerto Rico, LLC
Humacao, Puerto Rico 00791
Distributed by:
Solco Healthcare U.S., LLC
Humacao, Puerto Rico 00791.
500mg LabelRx Only

NDC 43547-222-15Dispense accompanying Medication Guide to each patient.
120 TabletsDispense in a tight, light resistant container with a child resistant closure.
Each tablet contains 500 mg of levetiracetam.
See enclosed package insert for dosage information.
Store at 25° C (77°F); excursions permitted to 15-30°C (59-86° F) [seeUSP Controlled Room Temperature].
Manufactured by:Legacy Pharmaceuticals Puerto Rico, LLCHumacao, Puerto Rico 00791Distributed by:Solco Healthcare U.S., LLCHumacao, Puerto Rico 00791.
750mg LabelRx OnlyNDC 43547-223-15Dispense accompanying Medication Guide to each patient.
120 TabletsDispense in a tight, light resistant container with a child resistant closure.
Each tablet contains 750 mg of levetiracetam.
See enclosed package insert for dosage information.
Store at 25° C (77°F); excursions permitted to 15-30°C (59-86° F) [seeUSP Controlled Room Temperature].
Manufactured by:Legacy Pharmaceuticals Puerto Rico, LLCHumacao, Puerto Rico 00791Distributed by:Solco Healthcare U.S., LLCHumacao, Puerto Rico 00791.
1000mg LabelRx OnlyNDC 43547-224-06Dispense accompanying Medication Guide to each patient.
60 TabletsDispense in a tight, light resistant container with a child resistant closure.
Each tablet contains 1000 mg of levetiracetam.
See enclosed package insert for dosage information.
Store at 25° C (77°F); excursions permitted to 15-30°C (59-86° F) [seeUSP Controlled Room Temperature].
Manufactured by:Legacy Pharmaceuticals Puerto Rico, LLCHumacao, Puerto Rico 00791Distributed by:Solco Healthcare U.S., LLCHumacao, Puerto Rico 00791.
Distributed by: Solco Healthecare US, LLC

Source: http://www.solcohealthcare.com/PDF/Product%20Insert%20Levetiracetam.pdf