NDC 14789-400 Levetiracetam

NDC Product Code 14789-400

NDC 14789-400-05

Package Description: 10 VIAL in 1 CARTON > 5 mL in 1 VIAL

This product is EXCLUDED from the official NDC directory because the listing data was inactivated by the FDA.

NDC Product Information

Levetiracetam with NDC 14789-400 is a product labeled by Nexus Pharmaceuticals Inc. The generic name of Levetiracetam is . The product's dosage form is and is administered via form.

Labeler Name: Nexus Pharmaceuticals Inc

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SODIUM CHLORIDE (UNII: 451W47IQ8X)
  • SODIUM ACETATE (UNII: 4550K0SC9B)
  • ACETIC ACID (UNII: Q40Q9N063P)
  • WATER (UNII: 059QF0KO0R)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Nexus Pharmaceuticals Inc
Labeler Code: 14789
Start Marketing Date: 06-03-2010 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2017 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: I - INACTIVATED, the listing data was inactivated by the FDA. What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

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Information for Patients

Levetiracetam

Levetiracetam is pronounced as (lee ve tye ra' se tam)

Why is levetiracetam medication prescribed?
Levetiracetam is used in combination with other medications to treat certain types of seizures in adults and children with epilepsy. Levetiracetam is in a class of medica...
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Levetiracetam Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

LEVETIRACETAM injection is an alternative for adult patients (16
years and older) when oral administration is temporarily not
feasible.

1.1 Partial Onset Seizures

LEVETIRACETAM is indicated as adjunctive therapy in the
treatment of partial onset seizures in adults with
epilepsy.

1.2 Myoclonic Seizures In Patients With Juvenile Myoclonic Epilepsy

LEVETIRACETAM is indicated as adjunctive therapy in the
treatment of myoclonic seizures in adults with juvenile
myoclonic epilepsy.

2.1 General Information

LEVETIRACETAM injection is for intravenous use only and
must be diluted prior to administration. LEVETIRACETAM injection
(500 mg/5 mL) should be diluted in 100 mL of a compatible
diluent [see Dosage and Administration
(2.7)] and
administered intravenously as a 15-minute IV
infusion.Product with particulate matter or discoloration should
not be used.Any unused portion of the LEVETIRACETAM injection vial
contents should be discarded.

2.2 Initial Exposure To Levetiracetam

LEVETIRACETAM can be initiated with either intravenous or
oral administration.Partial Onset
Seizures - In clinical trials of oral
LEVETIRACETAM, 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 (14.1)], 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 twice daily). 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
with LEVETIRACETAM tablets for periods of 6 months and longer.
There is no evidence that doses greater than 3000 mg/day confer
additional benefit.Myoclonic Seizures in Patients with
Juvenile Myoclonic Epilepsy -
Treatment should be initiated with a dose of 1000 mg/day, given
as twice-daily dosing (500 mg twice daily). 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.

2.3 Replacement Therapy

When switching from oral LEVETIRACETAM, the initial total
daily intravenous dosage of LEVETIRACETAM should be equivalent
to the total daily dosage and frequency of oral LEVETIRACETAM
and should be administered as a 15-minute intravenous infusion
following dilution in 100 mL of a compatible
diluent.

2.4 Switching To Oral Dosing

At the end of the intravenous treatment period, the
patient may be switched to LEVETIRACETAM oral administration at
the equivalent daily dosage and frequency of the intravenous
administration.

2.5 Dosing Instructions

LEVETIRACETAM injection is for intravenous use only and
must be diluted prior to administration. One vial of
LEVETIRACETAM injection contains 500 mg levetiracetam (500
mg/5mL). See Table 1 for the recommended preparation and
administration of LEVETIRACETAM injection to achieve a dose of
500 mg, 1000 mg, or 1500 mg.Table 1 : Preparation
and Administration of LEVETIRACETAM InjectionDose Withdraw
Volume Volume of
Diluent Infusion Time 500 mg 5 mL (5 mL
vial)100 mL15
minutes1000 mg10 mL (two 5 mL
vials)100 mL15 minutes 1500
mg 15 mL
(three 5 mL vials)100 mL15
minutesFor example, to prepare a 1000 mg dose, dilute 10 mL of
LEVETIRACETAM injection in 100 mL of a compatible diluent [
see Dosage and Administration (2.7)] and administer
intravenously as a 15-minute infusion.

2.6 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 2. 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:1. For female patients                      [140-age
(years)] x weight (kg)CLcr=
        
- - - - - - - - - - - - - - - - - - - - - -       
x 10.85
                  
  72 x serum creatinine (mg/dL)                    
1For female patients 1Following dialysis, a 250 to 500 mg
supplemental dose is recommended. Table 2 : Dosing
Adjustment Regimen for Adult Patients 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

2.7 Compatibility And Stability

LEVETIRACETAM injection was found to be physically
compatible and chemically stable when mixed with the following
diluents and antiepileptic drugs for at least 24 hours and
stored in polyvinyl chloride (PVC) bags at controlled room
temperature 15 to 30°C (59 to
86°F).DiluentsSodium chloride (0.9%) injection, USP
Lactated Ringer’s injection
Dextrose 5% injection, USPOther Antiepileptic
DrugsLorazepam
Diazepam
Valproate sodium
There is no data to support the physical compatibility of
LEVETIRACETAM injection with antiepileptic drugs that are not
listed above.Parenteral drug products should be inspected visually for
particulate matter and discoloration prior to administration
whenever solution and container permit.

3 Dosage Forms And Strengths

One vial of LEVETIRACETAM injection contains 500 mg levetiracetam
(500 mg/5 mL).

4 Contraindications

None

5.1 Neuropsychiatric Adverse Reactions

Partial Onset
Seizures - In some adults
experiencing partial onset seizures, LEVETIRACETAM causes the
occurrence of central nervous system adverse reactions 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 1-5 months
and resolved within 2-7 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.In addition, 4 (0.5%) of treated patients
attempted suicide compared to 0% of placebo patients.
One of these patients completed suicide. In the other 3
patients, the events did not lead to discontinuation or dose
reduction. The events occurred after patients had been treated
for between 4 weeks and 6 months [see Patient Counseling
Information (17)].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 reactions was more likely to occur in the
myoclonic seizure population. In some patients experiencing
myoclonic seizures, LEVETIRACETAM causes 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 patients 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.

5.2 Withdrawal Seizures

Antiepileptic drugs, including LEVETIRACETAM, should be
withdrawn gradually to minimize the potential of increased
seizure frequency.

5.3 Hematologic Abnormalities

Partial Onset
Seizures - 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
(≤2.8 x 109/L) decreased WBC, and 2.4% of
treated and 1.4% of placebo patients had at least one
possibly significant (≤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.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.

5.4 Hepatic Abnormalities

There were no meaningful changes in mean liver function
tests (LFT) in controlled trials in adult patients; lesser LFT
abnormalities were similar in drug and placebo treated patients
in controlled trials (1.4%). No patients were
discontinued from controlled trials for LFT abnormalities except
for 1 (0.07%) adult epilepsy patient receiving open
treatment.

5.5 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.

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates
in the clinical trials of another drug and may not reflect the
rates observed in practice.The adverse reactions that result from LEVETIRACETAM
injection use include all of those reported for LEVETIRACETAM
tablets and oral solution. Equivalent doses of intravenous (IV)
levetiracetam and oral levetiracetam result in equivalent Cmax,
Cmin, and total systemic exposure to levetiracetam when the IV
levetiracetam is administered as a 15 minute infusion. The
prescriber should be aware that the adverse reaction 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 reaction incidences in the population
studied.Partial Onset
Seizures - In well-controlled clinical
studies using LEVETIRACETAM tablets in adults with partial onset
seizures, the most frequently reported adverse reactions in
patients receiving LEVETIRACETAM in combination with other AEDs,
not seen at an equivalent frequency among placebo-treated
patients, were somnolence, asthenia, infection and dizziness. Of
the most frequently reported adverse reactions in
placebo-controlled studies using LEVETIRACETAM tablets in adults
experienc ing partial onset seizures, asthenia, somnolence and
dizziness appeared to occur predominantly during the first 4
weeks of treatment with LEVETIRACETAM.Table 3 lists treatment-emergent adverse reactions that
occurred in at least 1% of adult epilepsy patients
treated with LEVETIRACETAM tablets participating in
placebo-controlled studies and were numerically more common than
in patients treated with placebo. In these studies, either
LEVETIRACETAM or placebo was added to concurrent AED therapy.
Adverse reactions were usually mild to moderate in
intensity. Table 3: Incidence (%) of
Treatment-Emergent Adverse Reactions in
Placebo-Controlled, Add-On Studies
in Adults Experiencing Partial
Onset Seizures by Body System (Adverse
Reactions Occurred in at Least 1% of
LEVETIRACETAM-Treated Patients and Occurred More
Frequently than Placebo-Treated
Patients) Body
System/   Adverse
Reaction 
LEVETIRACETAM
(N=769) % 
Placebo (N=439) % Body as a Whole           Asthenia 15 9  
Headache 1413   
Infection 138   
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 Myoclonic
Seizures - Although the pattern of
adverse reactions in this study seems somewhat different from
that seen in patients with partial seizures, this is likely due
to the much smaller number of patients in this study compared to
partial seizure studies. The adverse reaction pattern for
patients with JME is expected to be essentially the same as for
patients with partial seizures.In the well-controlled clinical study using LEVETIRACETAM
tablets in patients with myoclonic seizures, the most frequently
reported adverse reactions in patients using LEVETIRACETAM in
combination with other AEDs, not seen at an equivalent frequency
among placebo-treated patients, were somnolence, neck pain, and
pharyngitis.Table 4 lists treatment-emergent adverse reactions that
occurred in at least 5% of juvenile myoclonic epilepsy
patients experiencing myoclonic seizures treated with
LEVETIRACETAM tablets 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 reactions were usually mild to moderate in
intensity. Table 4: Incidence (%) of
Treatment-Emergent Adverse Reactions in a
Placebo-Controlled, Add-On Study
in Patients with
Myoclonic Seizures by Body System
(Adverse Reactions Occurred in at Least 5%
of LEVETIRACETAM-Treated Patients and Occurred
More Frequently than Placebo-Treated
Patients) Body
System/   Adverse
Reaction 
LEVETIRACETAM
(N=60) % 
Placebo (N=60) % Ear and labyrinth
disorders          
Vertigo 5 3Infections and
infestations      Pharyngitis 70   
Influenza 5 2 Musculoskeletal and connective tissue
disorders       Neck
pain 8 2 Nervous
System disorders     
Somnolence 12 2 Psychiatric
disorders      
Depression 5 2 Discontinuation or Dose
Reduction in Well-Controlled Clinical StudiesPartial Onset
Seizures - In well-controlled adult
clinical studies using LEVETIRACETAM tablets, 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 5 lists the most common
(>1%) adverse reactions that resulted in
discontinuation or dose reduction and that occurred more
frequently in LEVETIRACETAM-treated patients than in
placebo-treated patients.Table 5: Adverse
Reactions that Most Commonly Resulted in
Discontinuation or Dose Reduction that Occurred More
Frequently in LEVETIRACETAM-Treated Patients in
Placebo-Controlled Studies in Adult Patients
Experiencing Partial Onset Seizures Adverse
ReactionLEVETIRACETAM
(N=769) n
(%)Placebo (N=439) n
(%)Asthenia 10 (1.3%) 3 (0.7%) Dizziness 11 (1.4%) 0 Somnolence 34 (4.4%) 7 (1.6%) Myoclonic
Seizures - In the placebo-controlled
study using LEVETIRACETAM tablets, 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 reactions that led to discontinuation
or dose reduction in the well-controlled study and that occurred
more frequently in LEVETIRACETAM-treated patients than in
placebo-treated patients are presented in Table 6.Table 6: Adverse
Reactions that Resulted in Discontinuation or Dose
Reduction that Occurred More Frequently in
LEVETIRACETAM-Treated Patients in
the Placebo-Controlled Study in
Patients with Juvenile Myoclonic
Epilepsy Adverse
ReactionLEVETIRACETAM
(N=60) n
(%)Placebo (N=60) n
(%) 
Anxiety2 (3.3%) 1 (1.7%) Depressed mood 1 (1.7%) 0 Depression 1 (1.7%) 0 Diplopia1 (1.7%)0Hypersomnia1 (1.7%)0Insomnia1 (1.7%)0Irritability1 (1.7%)0Nervousness1 (1.7%)0Somnolence1 (1.7%)0This study was too small to adequately characterize the
adverse reactions leading to discontinuation. It is expected
that the adverse reactions that would lead to discontinuation in
this population would be similar to those resulting in
discontinuation in other epilepsy trials (see tables 5 -
6).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.

6.2 Postmarketing Experience

The following adverse events have been identified during
postapproval use of LEVETIRACETAM. Because these events are
reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or
establish a casual relationship to drug exposure.In addition to the adverse reactions listed above
[see Adverse Reactions (6.1)], the following adverse events
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 majority of cases where LEVETIRACETAM
was discontinued. There have been reports of suicidal behavior
(including completed suicide, suicide attempt and suicidal
ideation) with marketed LEVETIRACETAM [see
Patient Counseling Information
(17)].

7.1 General Information

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.

7.2 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.

7.3 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.

7.4 Other Antiepileptic Drug

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.

7.5 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.

7.6 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.

7.7 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.

7.8 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.

8.1 Pregnancy

Pregnancy Category
C -
There are no adequate and well-controlled studies in pregnant
women. In animal studies, levetiracetam produced evidence of
developmental toxicity, including teratogenic effects, at doses
similar to or greater than human therapeutic doses.
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.Administration to female rats throughout pregnancy and
lactation led to increased incidences of minor fetal skeletal
abnormalities and 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/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.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 ≥600 mg/kg/day (approximately 4 times MRHD on a
mg/m2 basis) 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). Maternal toxicity 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
fetal skeletal variations was increased at a dose of 3600
mg/kg/day (12 times the MRHD). 1200 mg/kg/day (4 times the MRHD)
was a developmental no effect dose. There was no evidence of
maternal toxici ty 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).Patients may enroll in the North American Antiepileptic
Drug Pregnancy Registry by calling (888) 233-2334 (toll
free).

8.2 Labor And Delivery

The effect of LEVETIRACETAM on labor and delivery in
humans is unknown.

8.3 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.

8.4 Pediatric Use

Safety and effectiveness of
LEVETIRACETAM injection in patients below the age of 16
years have not been established.

8.5 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 61-88 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.

8.6 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 (12.3) and
Dosage and Administration (2.6)].

9 Drug Abuse And Dependence

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

10 Overdosage

Signs, Symptoms and Laboratory Findings of
Acute Overdosage in
Humans The highest known dose of oral LEVETIRACETAM received in the
clinical development program was 6000 mg/day. Other than drowsiness,
there were no adverse reactions in the few known cases of overdose in
clinical trials. Cases of somnolence, agitation, aggression, depressed
level of consciousness, respiratory depression and coma were observed
with LEVETIRACETAM overdoses in postmarketing use.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.

11 Description

LEVETIRACETAM injection is an antiepileptic drug available as a
clear, colorless, sterile solution (100 mg/mL) for intravenous
administration.The chemical name of levetiracetam, a single enantiomer, is
(-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular
formula is C8H14N2O2 and its
molecular weight is 170.21. Levetiracetam is chemically unrelated to
existing antiepileptic drugs (AEDs). It has the following structural
formula: Levetiracetam is a white to off-white crystalline powder with a
faint odor and a bitter taste. It is very soluble in water (104.0 g/100
mL). It is freely soluble in chloroform (65.3 g/100 mL) and in methanol
(53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble
in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane.
(Solubility limits are expressed as g/100 mL solvent.)LEVETIRACETAM injection contains 100 mg of levetiracetam per mL.
It is supplied in single-use 5 mL vials containing 500 mg levetiracetam,
water for injection, 45 mg sodium chloride, and buffered at
approximately pH 5.5 with glacial acetic acid and 8.2 mg sodium acetate
trihydrate. LEVETIRACETAM injection must be diluted prior to intravenous
infusion [see
Dosage and Administration (2.1)].

12.1 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 10μM
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 current s 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.

12.3 Pharmacokinetics

Equivalent doses of intravenous (IV) levetiracetam and
oral levetiracetam result in equivalent Cmax, Cmin, and total
systemic exposure to levetiracetam when the IV levetiracetam is
administered as a 15 minute infusion.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 injection and tablets are
bioequivalent. The pharmacokinetics of levetiracetam are linear
and time-invariant, with low intra- and inter-subject
variability. Levetiracetam is not significantly protein-bound
(<10% bound) and its volume of distribution is
close to the volume of intracellular and extracellular water.
Sixty-six percent (66%) of the dose is renally excreted
unchanged. The major metabolic pathway of levetiracetam
(24% of dose) is an enzymatic hydrolysis of the
acetamide group. It is not liver cytochrome P450 dependent. The
metabolites have no known pharmacological activity and are
renally excreted. Plasma half-life of levetiracetam across
studies is approximately 6-8 hours. It is increased in the
elderly (primarily due to impaired renal clearance) and in
subjects with renal impairment.Distribution - The equivalence of
levetiracetam injection and the oral formulation was
demonstrated in a bioavailability study of 17 healthy
volunteers. In this study, levetiracetam 1500 mg was diluted in
100 mL 0.9% sterile saline solution and was infused over
15 minutes. The selected infusion rate provided plasma
concentrations of levetiracetam at the end of the infusion
period similar to those achieved at Tmax after an equivalent
oral dose. It is demonstrated that levetiracetam 1500 mg
intravenous infusion is equivalent to levetiracetam 3 x 500 mg
oral tablets. The time independent pharmacokinetic profile of
levetiracetam was demonstrated following 1500 mg intravenous
infusion for 4 days with BID dosing. The AUC(0-12) at
steady-state was equivalent to AUCinf following an equivalent
single dose. 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, route of administration 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 Use in
Specific Populations (8.6) and Dosage and Administration
(2.6)].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 Drug Interactions (7)].Special PopulationsElderly - 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
- Safety and effectiveness of
LEVETIRACETAM injection in patients below the age of 16 years
have not been establishedGender -
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 >80mL/min). Approximately 50% of the pool
of levetiracetamin 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 Dosage
and Administration (2.6)].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.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis
- Rats were dosed with levetiracetam in the
diet for 104 weeks at doses of 50, 300 and 1800 mg/kg/day. The
highest dose corresponds to 6 times the maximum recommended
daily human dose (MRHD) of 3000 mg on a mg/m2 basis
and it also provided systemic exposure (AUC) approximately 6
times that achieved in humans receiving the MRHD. There was no
evidence of carcinogenicity. A study 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 potential for a
carcinogenic response has not been fully evaluated in that
species because adequate doses have not been
studied.Mutagenesis -
Levetiracetam was not mutagenic in the Ames test or in mammalian
cells in vitro in the Chinese hamster
ovary/HGPRT locus assay. It was not clastogenic in an in vitro
analysis of metaphase chromosomes
obtained from Chinese hamster ovary cells or in an in vivo
mouse micronucleus assay. The hydrolysis
product and major human metabolite of levetiracetam (ucb L057)
was not mutagenic in the Ames test or the in vitro
mouse lymphoma assay.Impairment of
Fertility - No adverse effects on male
or female fertility or reproductive performance were observed in
rats at doses up to 1800 mg/kg/day (approximately 6 times the
maximum recommended human dose on a mg/m2 or exposure
basis).

13.2 Animal Pharmacology And/Or Toxicology

Ln animal studies, levetiracetam produced evidence of
developmental toxicity at doses similar to or greater than human
therapeutic doses.

14 Clinical Studies

All efficacy trials utilized oral formulations. The
recommendation for the parenteral formulation is based upon these
studies as well as the demonstration of comparable bioavailability of
the oral and the parenteral formulation [see Pharmacokinetics
(12.3)].In the following studies, statistical significance versus placebo
indicates a p value < 0.05.

14.1 Partial Onset Seizures

Effectiveness in Partial Onset
Seizures in Adults with Epilepsy
-The effectiveness of LEVETIRACETAM as adjunctive therapy (added
to other antiepileptic drugs) in adults was established in three
multicenter, randomized, double-blind, placebo-controlled
clinical studies in patients who had refractory partial onset
seizures with or without secondary generalization. The tablet
formulation was used in all these studies. In these studies, 904
patients were randomized to placebo, 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.The criteria for statistical significance in all studies
was a p value < 0.05.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 7.Table 7: Reduction in Mean Over Placebo
in Weekly Frequency of Partial Onset Seizures in
Study 1  Placebo LEVETIRACETAM LEVETIRACETAM  (N=95) 1000 mg/day 3000 mg/day   (N=97) (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* Statistically significant versus
placeboStudy 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 8. Table 8: Reduction in Mean Over Placebo
in Weekly Frequency of Partial Onset Seizures in
Study 2: Period A  Placebo LEVETIRACETAM LEVETIRACETAM   1000 mg/day 2000 mg/day  (N=111) (N=106) (N=105)  Percent reduction in partial
seizure frequency over
placebo - 17.1%* 21.4%*  * Statistically
significant versus
placebo    The percentage of patients (y-axis) who achieved
≥50% reduction in weekly seizure rates from
baseline in partial onset seizure frequency over the entire
randomized treatment period (titration + evaluation period)
within the three treatment groups (x-axis) is presented in
Figure 2.Figure 2: Responder Rate
(≥50% Reduction from Baseline) in
Study 2: Period A
* 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 3Study 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). Secondary
outcome variables included the responder rate (incidence of
patients with ≥50% reduction from baseline in
partial onset seizure frequency). Table 9 displays the results
of the analysis of Study 3.Table 9: Reduction in Mean Over Placebo
in Weekly Frequency of Partial Onset Seizures in
Study 3  Placebo LEVETIRACETAM  3000 mg/day  (N=104) (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 * Statistically significant versus
placebo

14.2 Myoclonic Seizures In Patients With Juvenile Myoclonic Epilepsy

Effectiveness in Myoclonic Seizures in
Patients with Juvenile Myoclonic Epilepsy
(JME) The effectiveness
of LEVETIRACETAM as adjunctive therapy (added to other
antiepileptic drugs) in patients 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
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 10 displays
the results for the 113 patients with JME in this
study. Table 10:
Responder Rate (≥50% Reduction
from Baseline) in Myoclonic Seizure Days per Week
for Patients with JME  Placebo LEVETIRACETAM  (N=59) (N=54)        
Percentage of
responders 23.7% 60.4%*     
* Statistically significant
versus
placebo

16.1 How Supplied

LEVETIRACETAM (500 mg/5 mL injection is a clear,
colorless, sterile solution. It is supplied in single-use 5 mL
vials, available in cartons of 10 vials (NDC
14789-400-05).

16.2 Storage

Store at 25°C (77°F); excursions
permitted to 15 to 30°C (59 to 86°F) [see USP
Controlled Room Temperature].

17 Patient Counseling Information

Patients should be advised to notify their physician if they are
pregnant prior to therapy.Patients should be advised that LEVETIRACETAM may cause dizziness
and somnolence. Accordingly, patients should be advised not to drive or
operate heavy 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.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. LEVETIRACETAM Injection is manufactured in the USA for Nexus
Pharmaceuticals Inc., Vernon Hills, IL 60061

* Please review the disclaimer below.