These Highlights Do Not Include All The Information Needed To Use Levetiracetam In Sodium Chloride Injection Safely And Effectively. See Full Prescribing Information For Levetiracetam In Sodium Chloride Injection.

Partial-Onset Seizures

In clinical trials of oral levetiracetam, daily doses of 1,000 mg, 2,000 mg, and 3,000 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 1,000 mg/day, given as twice-daily dosing (500 mg twice daily). Additional dosing increments may be given (1,000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3,000 mg. Doses greater than 3,000 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 3,000 mg/day confer additional benefit.

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL - BAG

NDC 70860-602-41

Levetiracetam in 0.82% Sodium Chloride Injection

500 mg per 100 mL (5 mg per mL)

Rx only

For Intravenous Infusion Only

INFUSE OVER A PERIOD OF 15 MINUTES

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

Sterile, Nonpyrogenic, Preservative-free, PVC-free.

The container closure is not made with natural rubber latex.

Levetiracetam in Sodium Chloride Injection is an antiepileptic drug available as a clear, colorless, sterile solution for intravenous administration.

The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C ₈H ₁₄N ₂O ₂and 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 in Sodium Chloride Injection is a clear, colorless, sterile solution that is available in a single-dose dual port bag with an aluminum overwrap. The container closure is not made with natural rubber latex.

500 mg per 100 mL:One 100 mL bag contains 500 mg of levetiracetam (5 mg per mL), water for injection, 820 mg sodium chloride, 5.5 mg of glacial acetic acid and buffered at approximately pH 5.5 with glacial acetic acid and 164 mg sodium acetate trihydrate.

1,000 mg per 100 mL:One 100 mL bag contains 1,000 mg of levetiracetam (10 mg per mL), water for injection, 750 mg sodium chloride, 6.5 mg of glacial acetic acid and buffered at approximately pH 5.5 with glacial acetic acid and 164 mg sodium acetate trihydrate.

1,500 mg per 100 mL:One 100 mL bag contains 1,500 mg of levetiracetam (15 mg per mL), water for injection, 540 mg sodium chloride, 7.5 mg of glacial acetic acid and buffered at approximately pH 5.5 with glacial acetic acid and 164 mg sodium acetate trihydrate.

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.

Levetiracetam in Sodium Chloride Injection is supplied as follows:

Levetiracetam in Sodium Chloride Injection is a clear, colorless, sterile solution that is available in a single-dose 100 mL dual port bag with an aluminum overwrap.

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

There were 347 subjects in clinical studies of levetiracetam that were 65 years old 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.

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 [see Clinical Pharmacology ( 12.3)] .

All clinical studies supporting the efficacy of levetiracetam utilized oral formulations. The finding of efficacy of levetiracetam injection is based on the results of studies using an oral formulation of levetiracetam, and on the demonstration of comparable bioavailability of the oral and parenteral formulations [see Pharmacokinetics ( 12.3)] .

Levetiracetam in Sodium Chloride Injection is contraindicated in patients with a hypersensitivity to levetiracetam. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions ( 5.3)].

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

• Psychiatric Reactions [see Warnings and Precautions ( 5.1)]
• Somnolence and Fatigue [see Warnings and Precautions ( 5.2)]
• Anaphylaxis and Angioedema [see Warnings and Precautions ( 5.3)]
• Serious Dermatological Reactions [see Warnings and Precautions ( 5.4)]
• Coordination Difficulties [see Warnings and Precautions ( 5.5)]
• Withdrawal Seizures [see Warnings and Precautions ( 5.6)]
• Hematologic Abnormalities [see Warnings and Precautions ( 5.7)]
• Seizure Control During Pregnancy [see Warnings and Precautions ( 5.8)]

Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance [see Clinical Pharmacology ( 12.3)] . Dosage adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis [see Dosage and Administration ( 2.5)] .

Equivalent doses of intravenous (IV) levetiracetam and oral levetiracetam result in equivalent C _max, C _min, and total systemic exposure to levetiracetam when the IV levetiracetam is administered as a 15 minute infusion.

Levetiracetam in Sodium Chloride Injection is an antiepileptic drug indicated for adult patients (16 years and older) when oral administration is temporarily not feasible.

Levetiracetam in Sodium Chloride Injection is indicated for adjunct therapy in adults (≥16 years of age) with the following seizure types when oral administration is temporarily not feasible:

• Partial-onset seizures ( 1.1)
• Myoclonic seizures in patients with juvenile myoclonic epilepsy ( 1.2)
• Primary generalized tonic-clonic seizures ( 1.3)

As with most antiepileptic drugs, levetiracetam should be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. But if withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.

The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown.

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.

In some patients levetiracetam causes behavioral abnormalities. The incidences of behavioral abnormalities in the myoclonic and primary generalized tonic-clonic seizure studies were comparable to those of the adult partial-onset seizure studies.

A total of 13.3% of adult levetiracetam-treated patients compared to 6.2% of placebo patients experienced non- psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, and nervousness).

A total of 1.7% of adult levetiracetam-treated patients discontinued treatment due to behavioral adverse events, compared to 0.2% of placebo patients. The treatment dose was reduced in 0.8% of adult levetiracetam-treated patients and in 0.5% of placebo patients.

One percent of adult levetiracetam-treated patients experienced psychotic symptoms compared to 0.2% of placebo patients.

Two (0.3%) adult levetiracetam-treated patients were hospitalized and their treatment was discontinued due to psychosis. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation.

The above psychiatric signs and symptoms should be monitored.

Levetiracetam in Sodium Chloride Injection is indicated as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy.

• Psychiatric Reactions: Behavioral abnormalities including psychotic symptoms, suicidal ideation, irritability, and aggressive behavior have been observed. Monitor patients for psychiatric signs and symptoms ( 5.1)
• Somnolence and Fatigue: Monitor patients for these symptoms and advise patients not to drive or operate machinery until they have gained sufficient experience on levetiracetam ( 5.2)
• Serious Dermatological Reactions: Discontinue Levetiracetam at the first sign of rash unless clearly not drug related. ( 5.4)
• Coordination Difficulties: Monitor for ataxia, abnormal gait, and incoordination. ( 5.5)
• Withdrawal Seizures: Levetiracetam must be gradually withdrawn ( 5.6)

In some patients, levetiracetam causes somnolence and fatigue. The incidences of somnolence and fatigue provided below are from controlled adult partial-onset seizure studies. In general, the incidences of somnolence and fatigue in the myoclonic and primary generalized tonic-clonic studies were comparable to those of the adult partial-onset seizure studies.

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 3,000 mg/day. In a study where there was no titration, about 45% of patients receiving 4,000 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 levetiracetam- treated patients reported asthenia, compared to 9.1% of placebo patients. Treatment was discontinued due to asthenia 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 due to asthenia.

Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment.

Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery.

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.

The effectiveness of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in adults was established in three multicenter, randomized, double-blind, placebo-controlled clinical studies in patients who had refractory partial-onset seizures with or without secondary generalization. The tablet formulation was used in all these studies. In these studies, 904 patients were randomized to placebo, 1,000 mg, 2,000 mg, or 3,000 mg/day. Patients enrolled in Study 1 or Study 2 had refractory partial-onset seizures for at least two years and had taken two or more classical AEDs. Patients enrolled in Study 3 had refractory partial-onset seizures for at least 1 year and had taken one classical AED. At the time of the study, patients were taking a stable dose regimen of at least one and could take a maximum of two AEDs. During the baseline period, patients had to have experienced at least two partial-onset seizures during each 4-week period.

• For intravenous infusion only ( 2.1)
• Do not dilute prior to its use ( 2.1)
• Administer dose-specific bag intravenously over 15-minutes ( 2.1)

Initial Exposure to Levetiracetam

• Partial-Onset Seizures:Initial dose is 500 mg twice daily. Increase by 500 mg twice daily every 2 weeks to a maximum recommended dose of 1,500 mg twice daily. ( 2.2)
• Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy:Initial dose is 500 mg twice daily. Increase by 500 mg twice daily every 2 weeks to the recommended dose of 1,500 mg twice daily. ( 2.2)
• Primary Generalized Tonic-Clonic Seizures:Initial dose is 500 mg twice daily. Increase by 500 mg twice daily every 2 weeks to the recommended dose of 1,500 mg twice daily. ( 2.2)

Switching from or to oral Levetiracetam: The total daily dosage/frequency of levetiracetam injection should be equivalent to those of oral levetiracetam ( 2.3, 2.4)

Renal Impairment:Dose adjustment necessary based on creatinine clearance ( 2.5)

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.

Injection: Levetiracetam in Sodium Chloride Injection is a clear, colorless solution packaged in a single-dose bag and available in three strengths:

• 500 mg per 100 mL(5 mg per mL): 500 mg levetiracetam in 0.82% sodium chloride
• 1,000 mg per 100 mL(10 mg per mL): 1,000 mg levetiracetam in 0.75% sodium chloride
• 1,500 mg per 100 mL(15 mg per mL): 1,500 mg levetiracetam in 0.54% sodium chloride

The following adverse reactions have been identified during post-approval use of levetiracetam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In addition to the adverse reactions listed above [see Adverse Reactions ( 6.1)] , the following adverse reactions have been reported in patients receiving marketed levetiracetam worldwide. The listing is alphabetized: abnormal liver function test, acute kidney injury, agranulocytosis, anaphylaxis, angioedema, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, weight loss, and worsening of seizures. Alopecia has been reported with levetiracetam use; recovery was observed in majority of cases where levetiracetam was discontinued.

Coordination difficulties were only observed in the adult partial-onset seizure studies. A total of 3.4% of adult 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. These events occurred most frequently within the first 4 weeks of treatment.

Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery.

Levetiracetam can cause hematologic abnormalities. Hematologic abnormalities occurred in clinical trials and included decreases in white blood cell (WBC), neutrophil, and red blood cell counts (RBC); decreases in hemoglobin and hematocrit; and increases in eosinophil counts. Cases of agranulocytosis, pancytopenia, and thrombocytopenia have been reported in the postmarketing setting. A complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders.

• Pregnancy: Plasma levels of levetiracetam may be decreased; monitor closely during pregnancy. Based on animal data, may cause fetal harm. ( 5.8, 8.1)

Levetiracetam can cause anaphylaxis or angioedema after the first dose or at any time during treatment. Signs and symptoms in cases reported in the postmarketing setting with levetiracetam have included hypotension, hives, rash, respiratory distress, and swelling of the face, lip, mouth, eye, tongue, throat, and feet. In some reported cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of anaphylaxis or angioedema, levetiracetam should be discontinued and the patient should seek immediate medical attention. Levetiracetam should be discontinued permanently if a clear alternative etiology for the reaction cannot be established [see Contraindications ( 4)] .

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 C _max, C _min, and total systemic exposure to levetiracetam when the IV levetiracetam is administered as a 15-minute infusion.

Partial-Onset Seizures

In controlled clinical studies using levetiracetam tablets in adults with partial-onset seizures [see Clinical Studies ( 14.1)] , the most common adverse reactions in adult patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, asthenia, infection and dizziness.

Of the most common adverse reactions in adults experiencing partial-onset seizures, asthenia, somnolence and dizziness occurred predominantly during the first 4 weeks of treatment with levetiracetam.

Table 2lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving levetiracetam tablets 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.

In controlled adult clinical studies using levetiracetam tablets, 15% of patients receiving levetiracetam and 12% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. Table 3lists 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.

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.

Avoid abrupt withdrawal from levetiracetam in order to reduce the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions ( 5.6)].

Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients treated with levetiracetam. The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. Recurrence of the serious skin reactions following rechallenge with levetiracetam has also been reported. Levetiracetam should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy. This decrease is more pronounced during the third trimester. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy.

Levetiracetam can be initiated with either intravenous or oral administration.

Levetiracetam in Sodium Chloride Injection is for intravenous infusion only. It is available in the following concentrations: three single-dose 100 mL bags, each containing a different total dosage of levetiracetam (500 mg [5 mg per mL], 1,000 mg [10 mg per mL], or 1,500 mg [15 mg per mL]).

A single-dose bag should be administered intravenously over a 15-minute IV infusion period.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Levetiracetam in Sodium Chloride Injection should not be further diluted prior to use. Any unused portion of the Levetiracetam in Sodium Chloride Injection contents should be discarded.

Levetiracetam in Sodium Chloride Injection is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults with idiopathic generalized epilepsy.

The effectiveness of levetiracetam as adjunctive therapy in patients 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 3,000 mg/day for adults or a pediatric target dose of 60 mg/kg/day and treated at a stable dose of 3,000 mg/day (or 60 mg/kg/day for children) over 20 weeks (evaluation period). Study drug was given in 2 equally divided doses per day.

The primary measure of effectiveness was the percent reduction from baseline in weekly PGTC seizure frequency for levetiracetam and placebo treatment groups over the treatment period (titration + evaluation periods). There was a statistically significant decrease from baseline in PGTC frequency in the levetiracetam-treated patients compared to the placebo-treated patients.

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 4.

Figure 4: Responder Rate (≥50% Reduction from Baseline) in PGTC Seizure Frequency per Week

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 1. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in mL/min is needed.

Levetiracetam in Sodium Chloride Injection is found to be physically compatible and chemically stable for at least 24 hours when mixed with lorazepam, diazepam, and valproate sodium and stored at controlled room temperature 15°C to 30°C (59°F to 86°F).

There are no data to support the physical compatibility of levetiracetam injection with antiepileptic drugs that are not listed above.

Levetiracetam in Sodium Chloride Injection is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults with juvenile myoclonic epilepsy.

The effectiveness of levetiracetam as adjunctive therapy 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 3,000 mg/day and treated at a stable dose of 3,000 mg/day over 12 weeks (evaluation period). Study drug was given in 2 divided doses. The primary measure of effectiveness was the proportion of patients with at least 50% reduction in the number of days per week with one or more myoclonic seizures during the treatment period (titration + evaluation periods) as compared to baseline. Table 10displays the results for the 113 patients with JME in this study. Of 120 patients enrolled, 113 had a diagnosis of confirmed or suspected JME. The results are displayed in Table 10.

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

Partial-Onset Seizures

In clinical trials of oral levetiracetam, daily doses of 1,000 mg, 2,000 mg, and 3,000 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 1,000 mg/day, given as twice-daily dosing (500 mg twice daily). Additional dosing increments may be given (1,000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3,000 mg. Doses greater than 3,000 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 3,000 mg/day confer additional benefit.

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL - BAG

NDC 70860-602-41

Levetiracetam in 0.82% Sodium Chloride Injection

500 mg per 100 mL (5 mg per mL)

Rx only

For Intravenous Infusion Only

INFUSE OVER A PERIOD OF 15 MINUTES

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

Sterile, Nonpyrogenic, Preservative-free, PVC-free.

The container closure is not made with natural rubber latex.

Levetiracetam in Sodium Chloride Injection is an antiepileptic drug available as a clear, colorless, sterile solution for intravenous administration.

The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C ₈H ₁₄N ₂O ₂and 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 in Sodium Chloride Injection is a clear, colorless, sterile solution that is available in a single-dose dual port bag with an aluminum overwrap. The container closure is not made with natural rubber latex.

500 mg per 100 mL:One 100 mL bag contains 500 mg of levetiracetam (5 mg per mL), water for injection, 820 mg sodium chloride, 5.5 mg of glacial acetic acid and buffered at approximately pH 5.5 with glacial acetic acid and 164 mg sodium acetate trihydrate.

1,000 mg per 100 mL:One 100 mL bag contains 1,000 mg of levetiracetam (10 mg per mL), water for injection, 750 mg sodium chloride, 6.5 mg of glacial acetic acid and buffered at approximately pH 5.5 with glacial acetic acid and 164 mg sodium acetate trihydrate.

1,500 mg per 100 mL:One 100 mL bag contains 1,500 mg of levetiracetam (15 mg per mL), water for injection, 540 mg sodium chloride, 7.5 mg of glacial acetic acid and buffered at approximately pH 5.5 with glacial acetic acid and 164 mg sodium acetate trihydrate.

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.

Levetiracetam in Sodium Chloride Injection is supplied as follows:

Levetiracetam in Sodium Chloride Injection is a clear, colorless, sterile solution that is available in a single-dose 100 mL dual port bag with an aluminum overwrap.

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

There were 347 subjects in clinical studies of levetiracetam that were 65 years old 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.

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 [see Clinical Pharmacology ( 12.3)] .

All clinical studies supporting the efficacy of levetiracetam utilized oral formulations. The finding of efficacy of levetiracetam injection is based on the results of studies using an oral formulation of levetiracetam, and on the demonstration of comparable bioavailability of the oral and parenteral formulations [see Pharmacokinetics ( 12.3)] .

Levetiracetam in Sodium Chloride Injection is contraindicated in patients with a hypersensitivity to levetiracetam. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions ( 5.3)].

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

• Psychiatric Reactions [see Warnings and Precautions ( 5.1)]
• Somnolence and Fatigue [see Warnings and Precautions ( 5.2)]
• Anaphylaxis and Angioedema [see Warnings and Precautions ( 5.3)]
• Serious Dermatological Reactions [see Warnings and Precautions ( 5.4)]
• Coordination Difficulties [see Warnings and Precautions ( 5.5)]
• Withdrawal Seizures [see Warnings and Precautions ( 5.6)]
• Hematologic Abnormalities [see Warnings and Precautions ( 5.7)]
• Seizure Control During Pregnancy [see Warnings and Precautions ( 5.8)]

Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance [see Clinical Pharmacology ( 12.3)] . Dosage adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis [see Dosage and Administration ( 2.5)] .

Equivalent doses of intravenous (IV) levetiracetam and oral levetiracetam result in equivalent C _max, C _min, and total systemic exposure to levetiracetam when the IV levetiracetam is administered as a 15 minute infusion.

Levetiracetam in Sodium Chloride Injection is an antiepileptic drug indicated for adult patients (16 years and older) when oral administration is temporarily not feasible.

Levetiracetam in Sodium Chloride Injection is indicated for adjunct therapy in adults (≥16 years of age) with the following seizure types when oral administration is temporarily not feasible:

• Partial-onset seizures ( 1.1)
• Myoclonic seizures in patients with juvenile myoclonic epilepsy ( 1.2)
• Primary generalized tonic-clonic seizures ( 1.3)

As with most antiepileptic drugs, levetiracetam should be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. But if withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.

The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown.

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.

In some patients levetiracetam causes behavioral abnormalities. The incidences of behavioral abnormalities in the myoclonic and primary generalized tonic-clonic seizure studies were comparable to those of the adult partial-onset seizure studies.

A total of 13.3% of adult levetiracetam-treated patients compared to 6.2% of placebo patients experienced non- psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, and nervousness).

A total of 1.7% of adult levetiracetam-treated patients discontinued treatment due to behavioral adverse events, compared to 0.2% of placebo patients. The treatment dose was reduced in 0.8% of adult levetiracetam-treated patients and in 0.5% of placebo patients.

One percent of adult levetiracetam-treated patients experienced psychotic symptoms compared to 0.2% of placebo patients.

Two (0.3%) adult levetiracetam-treated patients were hospitalized and their treatment was discontinued due to psychosis. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation.

The above psychiatric signs and symptoms should be monitored.

Levetiracetam in Sodium Chloride Injection is indicated as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy.

• Psychiatric Reactions: Behavioral abnormalities including psychotic symptoms, suicidal ideation, irritability, and aggressive behavior have been observed. Monitor patients for psychiatric signs and symptoms ( 5.1)
• Somnolence and Fatigue: Monitor patients for these symptoms and advise patients not to drive or operate machinery until they have gained sufficient experience on levetiracetam ( 5.2)
• Serious Dermatological Reactions: Discontinue Levetiracetam at the first sign of rash unless clearly not drug related. ( 5.4)
• Coordination Difficulties: Monitor for ataxia, abnormal gait, and incoordination. ( 5.5)
• Withdrawal Seizures: Levetiracetam must be gradually withdrawn ( 5.6)

In some patients, levetiracetam causes somnolence and fatigue. The incidences of somnolence and fatigue provided below are from controlled adult partial-onset seizure studies. In general, the incidences of somnolence and fatigue in the myoclonic and primary generalized tonic-clonic studies were comparable to those of the adult partial-onset seizure studies.

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 3,000 mg/day. In a study where there was no titration, about 45% of patients receiving 4,000 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 levetiracetam- treated patients reported asthenia, compared to 9.1% of placebo patients. Treatment was discontinued due to asthenia 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 due to asthenia.

Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment.

Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery.

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.

The effectiveness of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in adults was established in three multicenter, randomized, double-blind, placebo-controlled clinical studies in patients who had refractory partial-onset seizures with or without secondary generalization. The tablet formulation was used in all these studies. In these studies, 904 patients were randomized to placebo, 1,000 mg, 2,000 mg, or 3,000 mg/day. Patients enrolled in Study 1 or Study 2 had refractory partial-onset seizures for at least two years and had taken two or more classical AEDs. Patients enrolled in Study 3 had refractory partial-onset seizures for at least 1 year and had taken one classical AED. At the time of the study, patients were taking a stable dose regimen of at least one and could take a maximum of two AEDs. During the baseline period, patients had to have experienced at least two partial-onset seizures during each 4-week period.

• For intravenous infusion only ( 2.1)
• Do not dilute prior to its use ( 2.1)
• Administer dose-specific bag intravenously over 15-minutes ( 2.1)

Initial Exposure to Levetiracetam

• Partial-Onset Seizures:Initial dose is 500 mg twice daily. Increase by 500 mg twice daily every 2 weeks to a maximum recommended dose of 1,500 mg twice daily. ( 2.2)
• Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy:Initial dose is 500 mg twice daily. Increase by 500 mg twice daily every 2 weeks to the recommended dose of 1,500 mg twice daily. ( 2.2)
• Primary Generalized Tonic-Clonic Seizures:Initial dose is 500 mg twice daily. Increase by 500 mg twice daily every 2 weeks to the recommended dose of 1,500 mg twice daily. ( 2.2)

Switching from or to oral Levetiracetam: The total daily dosage/frequency of levetiracetam injection should be equivalent to those of oral levetiracetam ( 2.3, 2.4)

Renal Impairment:Dose adjustment necessary based on creatinine clearance ( 2.5)

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.

Injection: Levetiracetam in Sodium Chloride Injection is a clear, colorless solution packaged in a single-dose bag and available in three strengths:

• 500 mg per 100 mL(5 mg per mL): 500 mg levetiracetam in 0.82% sodium chloride
• 1,000 mg per 100 mL(10 mg per mL): 1,000 mg levetiracetam in 0.75% sodium chloride
• 1,500 mg per 100 mL(15 mg per mL): 1,500 mg levetiracetam in 0.54% sodium chloride

The following adverse reactions have been identified during post-approval use of levetiracetam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In addition to the adverse reactions listed above [see Adverse Reactions ( 6.1)] , the following adverse reactions have been reported in patients receiving marketed levetiracetam worldwide. The listing is alphabetized: abnormal liver function test, acute kidney injury, agranulocytosis, anaphylaxis, angioedema, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, weight loss, and worsening of seizures. Alopecia has been reported with levetiracetam use; recovery was observed in majority of cases where levetiracetam was discontinued.

Coordination difficulties were only observed in the adult partial-onset seizure studies. A total of 3.4% of adult 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. These events occurred most frequently within the first 4 weeks of treatment.

Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery.

Levetiracetam can cause hematologic abnormalities. Hematologic abnormalities occurred in clinical trials and included decreases in white blood cell (WBC), neutrophil, and red blood cell counts (RBC); decreases in hemoglobin and hematocrit; and increases in eosinophil counts. Cases of agranulocytosis, pancytopenia, and thrombocytopenia have been reported in the postmarketing setting. A complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders.

• Pregnancy: Plasma levels of levetiracetam may be decreased; monitor closely during pregnancy. Based on animal data, may cause fetal harm. ( 5.8, 8.1)

Levetiracetam can cause anaphylaxis or angioedema after the first dose or at any time during treatment. Signs and symptoms in cases reported in the postmarketing setting with levetiracetam have included hypotension, hives, rash, respiratory distress, and swelling of the face, lip, mouth, eye, tongue, throat, and feet. In some reported cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of anaphylaxis or angioedema, levetiracetam should be discontinued and the patient should seek immediate medical attention. Levetiracetam should be discontinued permanently if a clear alternative etiology for the reaction cannot be established [see Contraindications ( 4)] .

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 C _max, C _min, and total systemic exposure to levetiracetam when the IV levetiracetam is administered as a 15-minute infusion.

Partial-Onset Seizures

In controlled clinical studies using levetiracetam tablets in adults with partial-onset seizures [see Clinical Studies ( 14.1)] , the most common adverse reactions in adult patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, asthenia, infection and dizziness.

Of the most common adverse reactions in adults experiencing partial-onset seizures, asthenia, somnolence and dizziness occurred predominantly during the first 4 weeks of treatment with levetiracetam.

Table 2lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving levetiracetam tablets 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.

In controlled adult clinical studies using levetiracetam tablets, 15% of patients receiving levetiracetam and 12% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. Table 3lists 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.

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.

Avoid abrupt withdrawal from levetiracetam in order to reduce the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions ( 5.6)].

Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients treated with levetiracetam. The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. Recurrence of the serious skin reactions following rechallenge with levetiracetam has also been reported. Levetiracetam should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy. This decrease is more pronounced during the third trimester. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy.

Levetiracetam can be initiated with either intravenous or oral administration.

Levetiracetam in Sodium Chloride Injection is for intravenous infusion only. It is available in the following concentrations: three single-dose 100 mL bags, each containing a different total dosage of levetiracetam (500 mg [5 mg per mL], 1,000 mg [10 mg per mL], or 1,500 mg [15 mg per mL]).

A single-dose bag should be administered intravenously over a 15-minute IV infusion period.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Levetiracetam in Sodium Chloride Injection should not be further diluted prior to use. Any unused portion of the Levetiracetam in Sodium Chloride Injection contents should be discarded.

Levetiracetam in Sodium Chloride Injection is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults with idiopathic generalized epilepsy.

The effectiveness of levetiracetam as adjunctive therapy in patients 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 3,000 mg/day for adults or a pediatric target dose of 60 mg/kg/day and treated at a stable dose of 3,000 mg/day (or 60 mg/kg/day for children) over 20 weeks (evaluation period). Study drug was given in 2 equally divided doses per day.

The primary measure of effectiveness was the percent reduction from baseline in weekly PGTC seizure frequency for levetiracetam and placebo treatment groups over the treatment period (titration + evaluation periods). There was a statistically significant decrease from baseline in PGTC frequency in the levetiracetam-treated patients compared to the placebo-treated patients.

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 4.

Figure 4: Responder Rate (≥50% Reduction from Baseline) in PGTC Seizure Frequency per Week

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 1. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in mL/min is needed.

Levetiracetam in Sodium Chloride Injection is found to be physically compatible and chemically stable for at least 24 hours when mixed with lorazepam, diazepam, and valproate sodium and stored at controlled room temperature 15°C to 30°C (59°F to 86°F).

There are no data to support the physical compatibility of levetiracetam injection with antiepileptic drugs that are not listed above.

Levetiracetam in Sodium Chloride Injection is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults with juvenile myoclonic epilepsy.

The effectiveness of levetiracetam as adjunctive therapy 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 3,000 mg/day and treated at a stable dose of 3,000 mg/day over 12 weeks (evaluation period). Study drug was given in 2 divided doses. The primary measure of effectiveness was the proportion of patients with at least 50% reduction in the number of days per week with one or more myoclonic seizures during the treatment period (titration + evaluation periods) as compared to baseline. Table 10displays the results for the 113 patients with JME in this study. Of 120 patients enrolled, 113 had a diagnosis of confirmed or suspected JME. The results are displayed in Table 10.

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