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Name:Levetiracetam
Manufacturer:Hetero Drugs Ltd.,
Category:Prescription Marketed Drugs


Levetiracetam Tablets

LEVETIRACETAM  - levetiracetam tablet, film coated 
Hetero Drugs Ltd.,

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Levetiracetam Tablets

DESCRIPTION


Levetiracetam is an antiepileptic drug available as 250 mg (blue), 500 mg (yellow),750 mg (orange), 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:

 

Structure

Levetiracetam is a white to off-white crystalline powder with a faint odor and a bitter taste. It is very soluble in water (1040 mg/mL). It is freely soluble in chloroform (653 mg/mL) and in methanol (536 mg/mL), soluble in ethanol (165 mg/mL), sparingly soluble in acetonitrile (57 mg/mL) and practically insoluble in n-hexane. (Solubility limits are expressed as mg/mL solvent.)

Levetiracetam tablets contain the labeled amount of levetiracetam. Inactive ingredients: corn starch, croscarmellose sodium, povidone, colloidal silicon dioxide, talc, magnesium stearate and additional agents listed below:

250 mg tablets: opadry II blue (polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, FD&C blue #2/indigo carmine aluminum lake)

500 mg tablets: opadry II yellow (polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, iron oxide yellow)

750 mg tablets:  opadry II orange (polyvinyl alcohol, titanium dioxide,  polyethylene glycol 3350, talc, FD&C yellow # 6/sunset yellow FCF aluminum lake, iron oxide red)

1000 mg tablets: opadry II white (polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc)

CLINICAL PHARMACOLOGY

Mechanism of Action

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

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

Levetiracetam at concentrations of up to 10 µMdid not demonstrate binding affinity for a variety of known receptors, such asthose 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 onneuronal voltage-gated sodium or T-type calcium currents and levetiracetam doesnot appear to directly facilitate GABAergic neurotransmission. However, in vitro studies have demonstrated thatlevetiracetam opposes the activity of negative modulators of GABA- andglycine-gated currents and partially inhibits N-type calcium currents inneuronal cells.

A saturable and stereoselective neuronal bindingsite in rat brain tissue has been described for levetiracetam. Experimentaldata indicate that this binding site is the synaptic vesicle protein SV2A,thought to be involved in the regulation of vesicle exocytosis. Although themolecular significance of levetiracetam binding to synaptic vesicle proteinSV2A is not understood, levetiracetam and related analogs showed a rank orderof affinity for SV2A which correlated with the potency of their antiseizureactivity in audiogenic seizure-prone mice. These findings suggest that theinteraction of levetiracetam with the SV2A protein may contribute to theantiepileptic 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 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 to 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 Tmaxby 1.5 hours. The pharmacokinetics of levetiracetam are linear over the dose range of 500 to 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 metabolized in humans. The major metabolic pathway is the enzymatic hydrolysis of the acetamide group, which produces the carboxylic acid metabolite, ucb L057 (24% of dose) and is not dependent on any liver cytochrome P450 isoenzymes. The major metabolite is inactive in animal seizure models. Two minor metabolites were identified as the product of hydroxylation of the 2-oxo-pyrrolidine ring (2% of dose) and opening of the 2-oxo-pyrrolidine ring in position 5 (1% of dose). There is no enantiomeric interconversion of levetiracetam or its major metabolite.

Elimination
 
Levetiracetam plasma half-life in adults is 7 ± 1 hour and is unaffected by either dose or repeated administration. Levetiracetam is eliminated from the systemic circulation by renal excretion as unchanged drug which represents 66% of administered dose. The total body clearance is 0.96 mL/min/kg and the renal clearance is 0.6 mL/min/kg. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. The metabolite ucb L057 is excreted by glomerular filtration and active tubular secretion with a renal clearance of 4 mL/min/kg. Levetiracetam elimination is correlated to creatinine clearance.
Levetiracetam clearance is reduced in patients with impaired renal function (see Special PopulationsRenal Impairmentand 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 subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above Cmax levels achieved within the therapeutic dose range, are neither inhibitors of, nor high affinity substrates for, human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.
 
Potential pharmacokinetic interactions of or with levetiracetam were assessed in clinical pharmacokinetic studies (phenytoin, valproate, warfarin, digoxin, oral contraceptive, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients (see PRECAUTIONS, Drug Interactions)
 
Special Populations
 
Elderly
Pharmacokinetics of levetiracetam were evaluated in 16 elderly subjects (age 61 to 88 years) with creatinine clearance ranging from 30 to 74 mL/min. Following oral administration of twice-daily dosing for 10 days, total body clearance decreased by 38% and the half-life was 2.5 hours longer in the elderly compared to healthy adults. This is most likely due to the decrease in renal function in these subjects.
 
Pediatric Patients

Pharmacokinetics of levetiracetam were evaluated in 24 pediatric patients (age 6 to12 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 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 L057) in 14 pediatric patients demonstrated rapid absorption of levetiracetam at all doses with a Tmax of about1 hour and a t½ 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 <30 mL/min). Clearance of levetiracetam is correlated with creatinine clearance.In anuric (end stage renal disease) patients, the total body clearance decreased 70% compared to normal subjects (CLcr >80 mL/min). Approximately 50% of the pool of levetiracetam in the body is removed during a standard 4-hour hemodialysis procedure.
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 <0.05.

Effectiveness In Partial Onset Seizures In Adults With Epilepsy

The effectiveness of levetiracetam as adjunctivetherapy (added to other antiepileptic drugs) in adults was established in threemulticenter, randomized, double-blind, placebo-controlled clinical studies inpatients who had refractory partial onset seizures with or without secondarygeneralization. The tablet formulation was used in all these studies. In thesestudies, 904 patients were randomized to placebo, 1000 mg, 2000 mg, or 3000mg/day. Patients enrolled in Study 1 or Study 2 had refractory partial onsetseizures 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 least1 year and had taken one classical AED. At the time of the study, patients weretaking a stable dose regimen of at least one and could take a maximum of twoAEDs. During the baseline period, patients had to have experienced at least twopartial 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 ≥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

 

 
Placebo
(N=95)
Levetiracetam 1000 mg/day
(N=97)
Levetiracetam 3000 mg/day
(N=101)
Percent reduction in partial seizure frequency over placebo
-
26.1%*
30.1%*
*statistically significant versus placebo

 


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

Figure 1: Responder Rate(≥ 50% Reduction From Baseline) In Study 1

Figure 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 ≥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

 

 
Placebo
(N=111)
Levetiracetam 1000 mg/day
(N=106)
Levetiracetam 2000 mg/day
(N=105)
Percent reduction in partial seizure frequency over placebo
-
17.1%*
21.4%*

  

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

Figure 2: Responder Rate(≥ 50% Reduction From Baseline) In Study 2: Period A

Figure 2

 

 *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 ≥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
 
Placebo
(N=104)
Levetiracetam 3000 mg/day
(N=180)
Percent reduction in partial seizure frequency over placebo
-
23.0%*

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

Figure 3: Responder Rate(≥ 50% Reduction From Baseline) In Study 3

Figure 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 ≥ 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

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

 

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

Figure 4: Responder Rate(≥ 50% Reduction From Baseline)

Figure 4 

 *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, double-blind, 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 in2 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) Levetiracetam(N=54)
Percentage of responders 23.7% 60.4%*

*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: Median Percent Reduction From Baseline In PGTC Seizure Frequency Per Week


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

*statistically significant versus placebo

The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in PGTC seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 5.

Figure 5: Responder Rate (≥50% Reduction From Baseline) In PGTC Seizure Frequency Per Week
Figure 5

*statistically significant versus placebo

INDICATIONS & USAGE


Levetiracetam Tablet 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 Tablet 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 Tablet 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,  increase  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  with  AEDs  and  persisted  for  the  duration  of  treatment assessed. Because most trials included in the 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 to 100 years) in the clinical trials analyzed. Table 7 shows absolute and relative risk by indication for all evaluated AEDs.                                                                                                               

Table 7  Risk by indication for antiepileptic drugs in the pooled analysis        

Indication
Placebo Patients with Events Per 1000 Patients
Drug Patients with Events Per 1000 Patients
Relative Risk : Incidence of Events in Drug Patients/Incidence in Placebo Patients
Risk Difference : Additional Drug Patients with Events Per 1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9

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 incoordination) 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 dose-response 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. Non-psychotic 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, non-psychotic 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 non-psychotic 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 pre-existent 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.

PRECAUTIONS

General Precautions

Hematologic Abnormalities

Partial Onset Seizures

Adults

Minor, but statistically significant, decreases compared toplacebo 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-treatedpatients in controlled trials.


Atotal of 3.2% of treated and 1.8% of placebo patients had at least one possiblysignificant (≤2.8 x 109/L)decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at leastone possibly significant (≤1.0 x 109/L) decreased neutrophil count. Ofthe treated patients with a low neutrophil count, all but one rose towards orto baseline with continued treatment. No patient was discontinued secondary tolow neutrophil counts.Pediatric Patients

Minor, but statistically significant, decreases in WBC andneutrophil counts were seen in levetiracetam-treatedpatients 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. Meanrelative lymphocyte counts increased by 1.7% in levetiracetam-treatedpatients, compared to a decrease of 4% in placebo patients (statisticallysignificant).

Inthe well-controlled trial, more levetiracetam-treatedpatients had a possibly clinically significant abnormally low WBC value (3.0% levetiracetam-treated versus 0% placebo), however, therewas no apparent difference between treatment groups with respect to neutrophilcount (5.0% levetiracetam-treated versus 4.2%placebo). No patient was discontinued secondary to low WBC or neutrophilcounts.

JuvenileMyoclonic Epilepsy

Although there were no obvious hematologic abnormalities observed inpatients with JME, the limited number of patients makes any conclusiontentative. The data from the partial seizure patients should be considered tobe relevant for JME patients.

 Hepatic Abnormalities

There were no meaningful changes in mean liver functiontests (LFT) in controlled trials in adult or pediatric patients; lesser LFTabnormalities were similar in drug and placebo treated patients in controlledtrials (1.4%). No adult or pediatric patients were discontinued from controlledtrials for LFT abnormalities except for 1 (0.07%) adult epilepsy patientreceiving 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. The Medication Guide may also be found in the full prescribing  information. Patients should be instructed to take levetiracetam only as prescribed.

Patients, their caregivers, and families should be counseled that AEDs, including levetiracetam, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,  or  the  emergence  of  suicidal thoughts,  behavior,  or  thoughts  about  self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Patients  should  be  advised  that  levetiracetam  may  cause  changes  in  behavior  (e.g.  aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability) and in rare cases patients may experience psychotic symptoms.

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant. 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.

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 (<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 Levetiracetum 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. Coadministration of this oral contraceptive did not influence the pharmacokinetics of levetiracetam.

Digoxin

Levetiracetam (1000 mg twice daily) did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every day. Coadministration of digoxin did not influence the pharmacokinetics of levetiracetam.

Warfarin

Levetiracetam (1000 mg twice daily) did not influence the pharmacokinetics of R and S warfarin. Prothrombin time was not affected by levetiracetam. Coadministration of warfarin did not affect the pharmacokinetics of levetiracetam.

Probenecid

Probenecid, a renal tubular secretion blocking agent, administered at a dose of 500 mg four times a day, did not change the pharmacokinetics of levetiracetam 1000 mg twice daily. 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 weeksat doses of 50, 300 and 1800 mg/kg/day. The highest dose corresponds to 6 timesthe maximum recommended daily human dose (MRHD) of 3000 mg on a mg/m2 basis andit also provided systemic exposure (AUC) approximately 6 times that achieved inhumans receiving the MRHD. There was no evidence of carcinogenicity. A studywas conducted in which mice received levetiracetam in the diet for 80 weeks atdoses of 60, 240 and 960 mg/kg/day (high dose is equivalent to 2 times the MRHDon a mg/m2or exposure basis). Although no evidence for carcinogenicity was seen, thepotential for a carcinogenic response has not been fully evaluated in thatspecies because adequate doses have not been studied.

Mutagenesis

Levetiracetam was not mutagenic in the Ames test or inmammalian cells in vitro in the Chinese hamsterovary/HGPRT locus assay. It was not clastogenic in an invitro analysis of metaphase chromosomes obtained from Chinese hamsterovary cells or in an in vivo mouse micronucleusassay. The hydrolysis product and major human metabolite of levetiracetam (ucbL057) was not mutagenic in the Ames test or the in vitromouse lymphoma assay.

Impairment Of Fertility

No adverse effects on male or female fertility orreproductive 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 exposurebasis).

 

Pregnancy

TeratogenicEffects:

Pregnancy Category C

In animal studies, levetiracetam produced evidence ofdevelopmental toxicity at doses similar to or greater than human therapeuticdoses.


Administration to female rats throughout pregnancy and lactationwas associated with increased incidences of minor fetal skeletal abnormalitiesand retarded offspring growth pre- and/or postnatally at doses ≥350 mg/kg/day(approximately equivalent to the maximum recommended human dose of 3000 mg[MRHD] on a mg/m2basis) and with increased pup mortality and offspring behavioral alterations ata dose of 1800 mg/kg/day (6 times the MRHD on a mg/m2 basis). The developmental noeffect dose was 70mg/kg/day (0.2 times the MRHD on a mg/m2 basis). There was no overtmaternal toxicity at the doses used in this study.

Treatmentof pregnant rabbits during the period of organogenesis resulted in increasedembryofetal mortality and increased incidences of minor fetal skeletalabnormalities at doses ≥600 mg/kg/day (approximately 4 times MRHD on a mg/m2 basis) andin decreased fetal weights and increased incidences of fetal malformations at adose of  1800 mg/kg/day (12 times theMRHD on a mg/m2basis). The developmental no effect dose was 200 mg/kg/day (1.3 times theMRHD on a mg/m2basis). Maternal toxicity was also observed at 1800 mg/kg/day.

Whenpregnant rats were treated during the period of organogenesis, fetal weightswere decreased and the incidence of fetal skeletal variations was increased ata dose of 3600 mg/kg/day (12 times the MRHD). 1200mg/kg/day (4 times the MRHD) was a developmental no effect dose. There was noevidence of maternal toxicity in this study.

Treatmentof rats during the last third of gestation and throughout lactation produced noadverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6times the MRHD on a mg/m2basis).

Thereare no adequate and well-controlled studies in pregnant women. Levetiracetam should be used during pregnancy only ifthe potential benefit justifies the potential risk to the fetus.

Pregnancy Registry

To provide information regardingthe effects of in utero exposure to levetiracetam, physicians are advised torecommend that pregnant patients taking levetiracetam enroll in the NorthAmerican Antiepileptic Drug (NAAED) pregnancy registry. This can be done bycalling the toll free number 1-888-233-2334, and must be done by the patientsthemselves. Informationontheregistry can also be found at the website http://www.aedpregnacyregistry.org/.

Labor & Delivery

The effect of levetiracetam onlabor and delivery in humans is unknown.

Nursing Mothers


Levetiracetam is excreted in breast milk. Because of thepotential for serious adverse reactions in nursing infants from levetiracetam, a decision should be made whether todiscontinue nursing or discontinue the drug, taking into account the importanceof the drug to the mother.

Pediatric Use

Safety and effectiveness in patients below 4 years of agehave not been established.

Studiesof levetiracetam in juvenile rats (dosing from day 4 through day 52 of age) anddogs (dosing from week 3 through week 7 of age) at doses of up to 1800mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommendedpediatric dose of 60 mg/kg/day on a mg/m2 basis) did not indicate apotential for age-specific toxicity.


Geriatric Use


Of the total number of subjectsin clinical studies of levetiracetam, 347 were 65 and over. No overalldifferences in safety were observed between these subjects and youngersubjects. There were insufficient numbers of elderly subjects in controlledtrials of epilepsy to adequately assess the effectiveness of levetiracetam in these patients.

Astudy in 16 elderly subjects (age 61 to 88 years) with oral administration ofsingle dose and multiple twice-daily doses for 10 days showed nopharmacokinetic differences related to age alone.

Levetiracetamis known to be substantially excreted by the kidney, and the risk of adversereactions to this drug may be greater in patients with impaired renal function.Because elderly patients are more likely to have decreased renal function, careshould be taken in dose selection, and it may be useful to monitor renalfunction.

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 PHARMACOLOGYand DOSAGE AND ADMINISTRATION, Adult Patients with Impaired Renal Function).

ADVERSE REACTIONS

The prescriber should be awarethat the adverse event incidence figures in the following tables, obtained whenlevetiracetam was added to concurrent AED therapy,cannot be used to predict the frequency of adverse experiences in the course ofusual medical practice where patient characteristics and other factors maydiffer from those prevailing during clinical studies. Similarly, the citedfrequencies cannot be directly compared with figures obtained from otherclinical investigations involving different treatments, uses, or investigators.An inspection of these frequencies, however, does provide the prescriber withone basis to estimate the relative contribution of drug and non-drug factors tothe adverse event incidences in the population studied.

Partial Onset Seizures

In well-controlled clinical studies in adults with partialonset seizures, the most frequently reported adverse events associated with theuse of levetiracetam in combination with other AEDs, not seen at an equivalentfrequency among placebo-treated patients, were somnolence, asthenia, infectionand dizziness. In the well-controlled pediatric clinical study in children 4 to16 years of age with partial onset seizures, the adverse events most frequentlyreported with the use of levetiracetam in combination with other AEDs, not seenat an equivalent frequency among placebo-treated patients, were somnolence,accidental injury, hostility, nervousness, and asthenia.

Table8 lists treatment-emergent adverse events that occurred in at least 1% of adultepilepsy patients treated with levetiracetamparticipating in placebo-controlled studies and were numerically more commonthan in patients treated with placebo. Table 9 lists treatment-emergent adverseevents that occurred in at least 2% of pediatric epilepsy patients (ages 4 to16 years) treated with levetiracetam participatingin the placebo-controlled study and were numerically more common than inpediatric patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AEDtherapy. Adverse events were usually mild to moderate in intensity.

Table 8: Incidence (%) Of Treatment-EmergentAdverse Events In Placebo-Controlled, Add-On Studies In Adults Experiencing PartialOnset Seizures By Body System (Adverse Events Occurred In At Least 1% Of Levetiracetam-TreatedPatients And Occurred More Frequently Than Placebo-Treated Patients)

 


Body System/
         Adverse Event
Levetiracetam
(N=769)
                 %
                 Placebo
(N=439)
                    %
Body as a Whole
 
 
            Asthenia
15
9
            Headache
14
13
            Infection
13
8
            Pain
7
6
Digestive System
 
 
            Anorexia
3
2
Nervous System
 
 
             Somnolence
15
8
            Dizziness
9
4
            Depression
4
2
            Nervousness
4
2
           Ataxia
3
1
           Vertigo
3
1
           Amnesia
2
1
           Anxiety
2
1
           Hostility
2
1
           Paresthesia
2
1
          Emotional Lability
2
0
Respiratory System
 
 
           Pharyngitis
6
4
           Rhinitis
4
3
           Cough Increased
2
1
           Sinusitis
2
1
 Special Senses    
          Diplopia
2
1

Otherevents reported by at least 1% of adult levetiracetam-treatedpatients but as or more frequent in the placebo group were the following:abdominal pain, accidental injury, amblyopia, arthralgia, back pain,bronchitis, chest pain, confusion, constipation, convulsion, diarrhea, druglevel increased, dyspepsia, ecchymosis, fever, flu syndrome, fungal infection,gastroenteritis, gingivitis, grand mal convulsion, insomnia, nausea, otitismedia, rash, thinking abnormal, tremor, urinary tract infection, vomiting andweight gain.

Table 9: Incidence (%) Of Treatment-EmergentAdverse Events In A Placebo-Controlled, Add-On Study In Pediatric Patients Ages4 to 16 Years Experiencing Partial Onset Seizures By Body System (Adverse EventsOccurred In At Least 2% Of Levetiracetam-TreatedPatients And Occurred More Frequently Than Placebo-Treated Patients)


Body System/Adverse Event

Levetiracetam
(N=101)%
Placebo
  (N=97)
  %

Body as a Whole
 
 
              Accidental Injury
17
10
             Asthenia
9
3
             Pain
6
3
             Flu Syndrome
3
2
             Face Edema
2
1
             Neck Pain
2
1
             Viral Infection
2
1
Digestive System
 
 
             Vomiting
15
13
             Anorexia
13
8
             Diarrhea
8
7
             Gastroenteritis
4
2
             Constipation
3
1
Hemic and Lymphatic System
 
 
             Ecchymosis
4
1
Metabolic and Nutritional
 
 
             Dehydration
2
1
Nervous System
 
 
              Somnolence
23
11
              Hostility
12
6
              Nervousness
10
2
              Personality Disorder
8
7
              Dizziness
7
2
              Emotional Lability
6
4
              Agitation
6
1
              Depression
3
1
              Vertigo
3
1
              Reflexes Increased
2
1
              Confusion
2
0
Respiratory System
 
 
              Rhinitis
13
8
              Cough Increased
11
7
               Pharyngitis
10
8
              Asthma
2
1
Skin and Appendages
 
 
              Pruritus
2
0
              Skin Discoloration
2
0
              Vesiculobullous Rash
2
0
Special Senses
 
 
             Conjunctivitis
3
2
             Amblyopia
2
0
             Ear Pain
2
0
Urogenital System
 
 
              Albuminuria
4
0
              Urine Abnormality
2
1


Other events occurring in at least 2% of pediatric levetiracetam-treated patients but as or more frequentin 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 (nototherwise specified), thinking abnormal, tremor, and urinary incontinence.

Myoclonic Seizures

Although the pattern of adverse events in this study seemssomewhat different from that seen in patients with partial seizures, this islikely due to the much smaller number of patients in this study compared topartial seizure studies. The adverse event pattern for patients with JME isexpected to be essentially the same as for patients with partial seizures.

In the well-controlled clinical study that included bothadolescent (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 combinationwith other AEDs, not seen at an equivalent frequency among placebo-treatedpatients, were somnolence, neck pain, and pharyngitis.

Table 10 lists treatment-emergent adverse events that occurredin at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonicseizures treated with levetiracetam and were numerically more common than in patients treatedwith placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverseevents were usually mild to moderate in intensity.

Table 10: Incidence (%) Of  Treatment-Emergent Adverse Events In APlacebo-Controlled, Add-On Study In Patients 12 Years Of Age And Older WithMyoclonic Seizures By Body System (Adverse Events Occurred In At Least 5% Of Levetiracetam-TreatedPatients And Occurred More Frequently Than Placebo-Treated Patients)

 


Body System /MedDRA preferred term
Levetiracetam

(N=60)
%
Placebo
(N=60)
%
Ear and labyrinth disorders
 
 
        Vertigo
5
3
Infections and infestations
 
 
        Pharyngitis
7
0
        Influenza
5
2
Musculoskeletal and connective tissue disorder
 
 
        Neck pain
8
2
Nervous system disorders
 
 
        Somnolence
12
2
Psychiatric disorders
 
 
        Depression
5
2

Other events occurring in at least 5% of levetiracetam-treated patients with myoclonic seizures but as or more frequent in theplacebo group were the following: fatigue and headache.

Primary Generalized Tonic-Clonic Seizures


Although the pattern of adverse events in this study seemssomewhat different from that seen in patients with partial seizures, this islikely due to the much smaller number of patients in this study compared topartial seizure studies. The adverse event pattern for patients with PGTCseizures is expected to be essentially the same as for patients with partialseizures.

 In the well-controlled clinical study that includedpatients 4 years of age and older with primary generalized tonic-clonic (PGTC)seizures, the most frequently reported adverse event associated with the use oflevetiracetam incombination with other AEDs, not seen at an equivalent frequency amongplacebo-treated patients, was nasopharyngitis.

Table 11 lists treatment-emergent adverseevents that occurred in at least 5% of idiopathic generalized epilepsy patientsexperiencing PGTC seizures treated with levetiracetamand were numerically more common than in patients treated with placebo. In thisstudy, either levetiracetam or placebo was addedto concurrent AED therapy. Adverse events were usually mild to moderate inintensity.

Table 11: Incidence (%) Of Treatment-Emergent Adverse Events In APlacebo-Controlled, Add-On Study In Patients 4 Years Of Age And Older With PGTCSeizures By MedDRA System Organ Class (Adverse Events Occurred In At Least 5%Of Levetiracetam-Treated Patients And Occurred More Frequently ThanPlacebo-Treated Patients)

MedDRA System Organ Class/ Preferred Term
Levetiracetam  (N=79) %
Placebo (N=84) %
Gastrointestinal disorders
8
7
        Diarrhea
 
 
General disorders and administration site conditions
 
 
        Fatigue
10
8
Infections and infestations
 
 
        Nasopharyngitis
14
5
Psychiatric disorders
 
 
        Irritability
6
2
        Mood swings
5
1

Other events occurring in at least 5% of levetiracetam-treated patients with PGTC seizures but as or more frequent in theplacebo group were the following: dizziness, headache, influenza, andsomnolence.

Time Course Of Onset Of Adverse Events For Partial Onset Seizures


Of the most frequently reported adverse eventsin adults experiencing partial onset seizures, asthenia, somnolence anddizziness appeared to occur predominantly during the first 4 weeks of treatmentwith levetiracetam.

Discontinuation Or Dose Reduction In Well-Controlled Clinical Studies

Partial Onset Seizures

In well-controlled adult clinical studies, 15.0% of patientsreceiving levetiracetam and 11.6% receivingplacebo either discontinued or had a dose reduction as a result of an adverseevent. Table 12 lists the most common (>1%) adverse events that resulted indiscontinuation or dose reduction.



Table12: Adverse Events That Most Commonly Resulted In Discontinuation Or DoseReduction In Placebo-Controlled Studies In Adult Patients Experiencing PartialOnset Seizures



Number (%)
 

   Levetiracetam
(N=769)

Placebo
(N=439)
Asthenia
10 (1.3%)
3 (0.7%)
Convulsion
23 (3.0%)
15 (3.4%)
Dizziness
11 (1.4%)
0
Rash
0
5 (1.1%)
Somnolence
34 (4.4%)
7 (1.6%)


Inthe 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. Theadverse events most commonly associated (≥3% in patients receiving levetiracetam) with discontinuation or dose reduction inthe well-controlled study are presented in Table 13.

Table 13: Adverse Events Most CommonlyAssociated With Discontinuation Or Dose Reduction In The Placebo-ControlledStudy In Pediatric Patients Ages 4 to 16 Years Experiencing Partial OnsetSeizures


 
Number (%)
 
Levetiracetam
(N=101)

Placebo
(N=97)
Asthenia
3 (3.0%)
0
Hostility
7 (6.9%)
2 (2.1%)
Somnolence
3 (3.0%)
3 (3.1%)

Myoclonic Seizures

In the placebo-controlled study, 8.3%of patients receiving levetiracetam and 1.7% receiving placebo eitherdiscontinued or had a dose reduction as a result of an adverse event. Theadverse events that led to discontinuation or dose reduction in thewell-controlled study are presented in Table 14.

Table 14: Adverse Events That Resulted In Discontinuation Or DoseReduction In The Placebo-Controlled Study In Patients With Juvenile MyoclonicEpilepsy


Body System/
        MedDRA preferred term
Levetiracetam
(N=60)
n (%)
Placebo

(N=60)

n (%)
Anxiety
2 (3.3%)
1 (1.7%)
Depressed mood
1 (1.7%)
0
Depression
1 (1.7%)
0
Diplopia
1 (1.7%)
0
Hypersomnia
1 (1.7%)
0
Insomnia
1 (1.7%)
0
Irritability
1 (1.7%)
0
Nervousness
1 (1.7%)
0
Somnolence
1 (1.7%)
0

PrimaryGeneralized Tonic-Clonic Seizures

In the placebo-controlled study, 5.1% of patients receivinglevetiracetam and 8.3% receiving placebo either discontinued or had a dosereduction during the treatment period as a result of a treatment-emergent adverseevent.


This study was too small to adequately characterize the adverse eventsleading to discontinuation. It is expected that the adverse events that wouldlead to discontinuation in this population would be similar to those resultingin discontinuation in other epilepsy trials (see tables 12 to 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 distributionof adverse experience reports by age and race.

Postmarketing Experience

Thefollowing adverse events have been identified during postapproval use oflevetiracetam. Because these events are reported voluntarily from a populationof uncertain size, it is not always possible to reliably estimate theirfrequency or establish a casual relationship to drug exposure.

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 suppressionidentified in some of these cases), thrombocytopenia, and weight loss. Alopeciahas been reported with levetiracetam use; recoverywas observed in majority of cases where levetiracetamwas discontinued. These adverse experiences have not been listed above, anddata are insufficient to support an estimate of their incidence or to establishcausation.

DRUG ABUSE AND DEPENDENCE

The abuse and dependence potential of levetiracetamhas not been evaluated in human studies.

 

CONTROLLED SUBSTANCE

OVERDOSAGE


Signs, Symptoms And Laboratory Findings Of Acute Overdosage In Humans

The highest known dose of levetiracetamreceived in the clinical development program was 6000 mg/day. Other thandrowsiness, there were no adverse events in the few known cases of overdose inclinical trials. Cases of somnolence, agitation, aggression, depressed level ofconsciousness, 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 unabsorbeddrug should be attempted by emesis or gastric lavage; usual precautions shouldbe observed to maintain airway. General supportive care of the patient isindicated including monitoring of vital signs and observation of the patient’sclinical status. A CertifiedPoison ControlCenter should becontacted for up to date information on the management of overdose with levetiracetam.

 

Hemodialysis

Standard hemodialysis procedures result in significantclearance of levetiracetam (approximately 50% in 4 hours) and should be consideredin cases of overdose. Although hemodialysis has not been performed in the fewknown cases of overdose, it may be indicated by the patient's clinical state orin patients with significant renal impairment.

DOSAGE & ADMINISTRATION

Levetiracetam Tablet isindicated as adjunctive treatment of partial onset seizures in adults andchildren 4 years of age and older with epilepsy.

Levetiracetam Tablet isindicated as adjunctive therapy in the treatment of myoclonic seizures inadults and adolescents 12 years of age and older with juvenile myoclonicepilepsy.


Levetiracetam Tablet is indicated as adjunctive therapy in the treatment ofprimary generalized tonic-clonic seizures in adults and children 6 years of ageand 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 <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 ≤ 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
 20 mg/kg/day
(BID dosing)
40 mg/kg/day
(BID dosing)
60 mg/kg/day
(BID dosing)
20.1 to 40 kg
     500 mg/day
(1 x 250 mg
tablet BID)
     1000 mg/day
(1 x 500 mg
tablet BID)
      1500 mg/day
(1 x 750 mg
tablet BID)
              >40 kg
 
     1000 mg/day
(1 x 500 mg
tablet BID)
     2000 mg/day
(2 x 500 mg
tablets BID)
      3000 mg/day
(2 x 750 mg
tablets BID)

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 beinitiated 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 dailydose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not beenstudied.

 

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 <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≤ 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 14 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 beindividualized according to the patient's renal function status. Recommendeddoses and adjustment for dose for adults are shown in Table 16. To use thisdosing table, an estimate of the patient's creatinine clearance (CLcr) inmL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL)determination using the following formula:

 

              [140-age(years)] x weight (kg)
CLcr = ———————————————— (x 0.85 for female patients)
                 72x serum creatinine (mg/dL)

Table 16: Dosing Adjustment Regimen For AdultPatients With  Impaired Renal Function

        Group
Creatinine Clearance
(mL/min)
Dosage
(mg)
Frequency
        Normal
> 80
500 to 1,500
Every 12 h
        Mild
50 to 80
500 to 1,000
Every 12 h
        Moderate
30 to 50
250 to 750
Every 12 h
        Severe
< 30
250 to 500
Every 12 h
     ESRD patients
   using dialysis
----
500 to 1,000
1Every 24 h

1Following dialysis, a 250 to 500 mg supplementaldose is recommended.

 

HOW SUPPLIED

Levetiracetam tablets, 250 mg are blue coloured, oblong shaped, scored, film coated tablets debossed with ‘H’ on one side and ‘87’ on other side. They are supplied in containers of

 30 tablets (NDC 65977-5036-0)

 60 tablets (NDC 65977-5036-1)

 120 tablets (NDC 65977-5036-2)

 500 tablets (NDC 65977-5036-3)

 1000 tablets (NDC 65977-5036-4)

 Levetiracetam tablets, 500 mg are yellow coloured, oblong shaped, scored, film coated tablets debossed with ‘H’ on one side and ‘88’ on other side. They are supplied in  containers of

 30 tablets (NDC 65977-5037-0)

 60 tablets (NDC 65977-5037-1)

 120 tablets (NDC 65977-5037-2)

 500 tablets (NDC 65977-5037-3)

 1000 tablets (NDC 65977-5037-4)

Levetiracetam tablets, 750 mg are orange coloured, oblong shaped, scored, film coated tablets debossed with ‘H’ on one side and ‘90’ on other side. They are supplied in containers of

 30 tablets (NDC 65977-5038-0)

 60 tablets (NDC 65977-5038-1)

120 tablets (NDC 65977-5038-2)

500 tablets (NDC 65977-5038-3)


Levetiracetam tablets, 1000 mg are white coloured, oblong shaped, scored, film coated tablets debossed with ‘H’ on one side and ‘91’ on other side. They are supplied in containers of

30 tablets (NDC 65977-5039-0)

60 tablets (NDC 65977-5039-1)

120 tablets (NDC 65977-5039-2)

500 tablets (NDC 65977-5039-3)

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container.

                                     Address

                                                                                                         

              

                                             

ANIMAL PHARMACOLOGY & OR TOXICOLOGY

SPL MEDGUIDE

 

MEDICATION GUIDE

 Levetiracetam Tablets

 Rx Only

 

Read this Medication Guidebefore you start taking levetiracetam and each time you get a refill. There may be new information. This informationdoes not take the place of talkingto your healthcare provider about your medical condition or treatment

 What is the most important information I shouldknow about levetiracetam?

 Like other antiepileptic drugs, levetiracetam may cause suicidal thoughts or actions in a very smallnumber of people, about 1 in 500 people taking it.

Call a healthcareprovider 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 commitsuicide

•      new or worsedepression

•      new or worse anxiety

•      feeling agitated orrestless

•      panic attacks

•      trouble sleeping(insomnia)

•      new or worseirritability

•      acting aggressive,being angry, or violent

•      acting on dangerous impulses

•      an extremeincrease in activity and talking (mania)

•      other unusual changesin behavior or mood

 

Do not stop levetiracetam without first talking to a healthcare provider.

•      Stopping levetiracetamsuddenly can cause serious problems. Stopping aseizure 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 checkfor other causes.

 How canI 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-upvisits with your healthcare provideras scheduled.

•      Call your healthcare providerbetween 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 people 4 years ofage and older with epilepsy

           •     myoclonic seizures in people 12 years ofage and older with juvenile myoclonic epilepsy

           •     primary generalized tonic-clonic seizuresin people 6 years of age and older with  certain types of generalized epilepsy.

 It is not known iflevetiracetam is safe or effectivein children under 4 years ofage.

Before taking your medicine,make sure you have received the correctmedicine. Comparethe name above with the name on your bottle and the appearance of your medicine with the description of levetiracetamprovided below. Contact your pharmacist immediately if you believe a dispensing error may have occurred.

Levetiracetamtablets, 250 mg are blue coloured, oblong shaped, scored, film coated tabletsdebossed with ‘H’ on one side and ‘87’ on other side.

 

Levetiracetamtablets, 500 mg are yellow coloured, oblong shaped, scored, film coated tabletsdebossed with ‘H’ on one side and ‘88’ on other side.

 

Levetiracetamtablets, 750 mg are orange coloured, oblong shaped, scored, film coated tabletsdebossed with ‘H’ on one side and ‘90’ on other side.

 

Levetiracetamtablets, 1000 mg are white coloured, oblong shaped, scored, film coated tabletsdebossed with ‘H’ on one side and ‘91’ on other side.

What should I tell my healthcare provider beforestarting levetiracetam?

Before taking 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 problems

•    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 shouldtake levetiracetam while you are pregnant.  If you  become pregnant while taking levetiracetam, talk to your healthcare provider about registering with the NorthAmerican Antiepileptic Drug Pregnancy Registry. You can enroll in this registryby calling 1-888-233-2334. The  purpose of this registry is tocollect information about the safety of  levetiracetam and otherantiepileptic medicine during the pregnancy.

•     are breast feeding.Levetiracetam can pass into your milk and may harm your baby. You and your healthcare provider should discusswhether you should take levetiracetam or breast-feed; you should not do both.

Tell your healthcare providerabout all the medicines you take, including prescription and nonprescription medicines,vitamins, and herbalsupplements.  Do not start a new medicine without first talking with your healthcare provider.

Know the medicinesyou take.   Keepa list of them to show your healthcare providerand pharmacist each time you get a new medicine.

How shouldI take levetiracetam?

Take levetiracetam exactly as prescribed.

•   Your healthcare provider will tell you how much levetiracetam to take and when to take it.Levetiracetam is usually taken twicea day.  Take levetiracetam at the same times each day.

•     Your healthcare providermay change your dose. Do not changeyour dose without talking to your healthcareprovider.

•     Take levetiracetam with or without food.

•     Swallow the tabletswhole. Do not chew or crush tablets.

•     If you miss a dose of levetiracetam, take it as soon as you remember. If it is almost time foryour 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?

 Do  not  drive, operate machinery  or  do  other  dangerous  activities  until  you  know howlevetiracetam affects you. Levetiracetam maymake you dizzy or sleepy.

What are the possible side effects oflevetiracetam?

•      See “What is the mostimportant information I should know about levetiracetam?”

Levetiracetam can cause serious side effects.

Call your healthcare provider right away if you haveany of these symptoms:

•  moodand behavior changessuch as aggression, agitation, anger, anxiety, apathy,mood swings, depression, hostility,and irritability.  A few people may get psychoticsymptoms such as hallucinations (seeing or hearing things that are really not there),delusions (false or strangethoughts or beliefs) and unusual behavior.

•    extreme sleepiness, tiredness, and weakness

•    problems with musclecoordination (problems walking andmoving)

The most common side effects seen in people whotake levetiracetam include:

•   sleepiness

•   weakness

•   dizziness

•   infection

The mostcommon side effects seen in childrenwho take levetiracetam include, in addition to those listed above:

•    accidental injury

•    irritability

•   hostility

These side effects can happen at any time but happen more often within thefirst 4 weeks of treatment except forinfection.

Tell your healthcare provider if you have any sideeffect that bothers you or that does not go away.

These are not all the possible side effects of levetiracetam.  For more information, ask your healthcareprovideror pharmacist.

Call your doctor for medical adviceabout side effects. You may reportside effects to FDA at 1-800-FDA-1088.

How should I store levetiracetam?

•    Store levetiracetam at room temperature, 20°C to 25°C (68°F to 77°F) awayfrom heat and light.

•    Keeplevetiracetam and all medicines out ofthe reach of children.

Generalinformation about levetiracetam.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.  Do not use levetiracetam for a condition for which it was not prescribed.Do not give levetiracetam to other people,even if they have the same symptoms that you have. It may harmthem.

This Medication Guide summarizes the most important information about levetiracetam. If you would like more information,talk with your healthcare provider.You can ask your pharmacist orhealthcare provider for information about levetiracetam that is writtenfor health professionals.

What are the ingredientsof levetiracetam?

Levetiracetam tablet active ingredient: levetiracetam

Inactive ingredients: corn starch, croscarmellose sodium, povidone, colloidal silicon dioxide, talc, magnesium stearate and additional agents listed below:


250mg tablets: opadry II blue (polyvinyl alcohol, titanium dioxide, polyethyleneglycol 3350, talc, FD&C blue #2/indigo carmine aluminum lake)

500mg tablets: opadry II yellow (polyvinyl alcohol, titanium dioxide, polyethyleneglycol 3350, talc, iron oxide yellow)

750mg tablets:  opadry II orange (polyvinylalcohol, titanium dioxide,  polyethyleneglycol 3350, talc, FD&C yellow #6/sunset yellow FCF aluminum lake, ironoxide red)

1000mg tablets: opadry II white (polyvinyl alcohol, titanium dioxide, polyethyleneglycol 3350, talc)

Levetiracetamdoes not contain lactose or gluten.


PACKAGE LABEL.PRINCIPAL DISPLAY PANEL


Levetiracetam Tablets 250 mg – 30s count
 
250 mg - 30s count

 
 
 Levetiracetam Tablets 500 mg – 30s count
 
500 mg - 30s count

 
 Levetiracetam Tablets 750 mg – 30s count
 
750 mg - 30s count

 
Levetiracetam Tablets 1000 mg – 30s count
 
 
1000 mg - 30s count

 
 
 
 
 
 

LEVETIRACETAM 
levetiracetam tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:65977-5036
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
LEVETIRACETAM (LEVETIRACETAM) LEVETIRACETAM 250 mg
Inactive Ingredients
Ingredient Name Strength
STARCH, CORN  
CROSCARMELLOSE SODIUM  
POVIDONE  
COLLOIDAL SILICON DIOXIDE  
TALC  
MAGNESIUM STEARATE  
Polyvinyl Alcohol  
TITANIUM DIOXIDE  
POLYETHYLENE GLYCOL 3350  
FD&C BLUE NO. 2  
Product Characteristics
Color BLUE Score 2 pieces
Shape OVAL (oblong shaped) Size 14mm
Flavor Imprint Code H;87
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:65977-5036-0 30 TABLET, FILM COATED (30 TABLET) in 1 BOTTLE None
2 NDC:65977-5036-1 60 TABLET, FILM COATED (60 TABLET) in 1 BOTTLE None
3 NDC:65977-5036-2 120 TABLET, FILM COATED (120 TABLET) in 1 BOTTLE None
4 NDC:65977-5036-3 500 TABLET, FILM COATED (500 TABLET) in 1 BOTTLE None
5 NDC:65977-5036-4 1000 TABLET, FILM COATED (1000 TABLET) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA090515 10/08/2010

LEVETIRACETAM 
levetiracetam tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:65977-5037
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
LEVETIRACETAM (LEVETIRACETAM) LEVETIRACETAM 500 mg
Inactive Ingredients
Ingredient Name Strength
STARCH, CORN  
CROSCARMELLOSE SODIUM  
POVIDONE  
COLLOIDAL SILICON DIOXIDE  
TALC  
MAGNESIUM STEARATE  
POLYVINYL ALCOHOL  
TITANIUM DIOXIDE  
POLYETHYLENE GLYCOL 3350  
FERRIC OXIDE YELLOW  
Product Characteristics
Color YELLOW Score 2 pieces
Shape OVAL (oblong shaped) Size 18mm
Flavor Imprint Code H;88
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:65977-5037-0 30 TABLET, FILM COATED (30 TABLET) in 1 BOTTLE None
2 NDC:65977-5037-1 60 TABLET, FILM COATED (60 TABLET) in 1 BOTTLE None
3 NDC:65977-5037-2 120 TABLET, FILM COATED (120 TABLET) in 1 BOTTLE None
4 NDC:65977-5037-3 500 TABLET, FILM COATED (500 TABLET) in 1 BOTTLE None
5 NDC:65977-5037-4 1000 TABLET, FILM COATED (1000 TABLET) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA090515 10/08/2010

LEVETIRACETAM 
levetiracetam tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:65977-5038
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
LEVETIRACETAM (LEVETIRACETAM) LEVETIRACETAM 750 mg
Inactive Ingredients
Ingredient Name Strength
STARCH, CORN  
CROSCARMELLOSE SODIUM  
POVIDONE  
COLLOIDAL SILICON DIOXIDE  
TALC  
MAGNESIUM STEARATE  
POLYVINYL ALCOHOL  
TITANIUM DIOXIDE  
POLYETHYLENE GLYCOL 3350  
FD&C YELLOW NO. 6  
FERRIC OXIDE RED  
Product Characteristics
Color ORANGE Score 2 pieces
Shape OVAL (oblong shaped) Size 19mm
Flavor Imprint Code H;90
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:65977-5038-0 30 TABLET, FILM COATED (30 TABLET) in 1 BOTTLE None
2 NDC:65977-5038-1 60 TABLET, FILM COATED (60 TABLET) in 1 BOTTLE None
3 NDC:65977-5038-2 120 TABLET, FILM COATED (120 TABLET) in 1 BOTTLE None
4 NDC:65977-5038-3 500 TABLET, FILM COATED (500 TABLET) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA090515 10/08/2010

LEVETIRACETAM 
levetiracetam tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:65977-5039
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
LEVETIRACETAM (LEVETIRACETAM) LEVETIRACETAM 1000 mg
Inactive Ingredients
Ingredient Name Strength
STARCH, CORN  
CROSCARMELLOSE SODIUM  
POVIDONE  
COLLOIDAL SILICON DIOXIDE  
TALC  
MAGNESIUM STEARATE  
POLYVINYL ALCOHOL  
TITANIUM DIOXIDE  
POLYETHYLENE GLYCOL 3350  
Product Characteristics
Color WHITE Score 2 pieces
Shape OVAL (oblong shaped) Size 21mm
Flavor Imprint Code H;91
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:65977-5039-0 30 TABLET, FILM COATED (30 TABLET) in 1 BOTTLE None
2 NDC:65977-5039-1 60 TABLET, FILM COATED (60 TABLET) in 1 BOTTLE None
3 NDC:65977-5039-2 120 TABLET, FILM COATED (120 TABLET) in 1 BOTTLE None
4 NDC:65977-5039-3 500 TABLET, FILM COATED (500 TABLET) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA090515 10/08/2010

Labeler - Hetero Drugs Ltd., (650229163)
Establishment
Name Address ID/FEI Operations
Hetero Drugs Limited 676162024 ANALYSIS, MANUFACTURE

Revised: 01/2011 Hetero Drugs Ltd.,



Source: http://dailymed.nlm.nih.gov
Reproduced with permission of U.S. National Library of Medicine


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