Levetiracetam

1 INDICATIONS AND USAGE 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) 1.1 Partial-Onset Seizures Levetiracetam in Sodium Chloride Injection 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 in Sodium Chloride Injection is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults with juvenile myoclonic epilepsy. 1.3 Primary Generalized Tonic-Clonic Seizures 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. 1.4 Limitations of Use Levetiracetam in Sodium Chloride Injection is an antiepileptic drug indicated for adult patients (16 years and older) when oral administration is temporarily not feasible.

2 DOSAGE AND ADMINISTRATION • 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). 2.1 General Information – 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/mL], 1000 mg [10 mg/mL], or 1500 mg [15 mg/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. 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 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. Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Treatment should be initiated with a dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased by 1,000 mg/day every 2 weeks to the recommended daily dose of 3,000 mg. The effectiveness of doses lower than 3,000 mg/day has not been studied. Primary Generalized Tonic-Clonic Seizures Treatment should be initiated with a dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased by 1,000 mg/day every 2 weeks to the recommended daily dose of 3,000 mg. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied. 2.3 Switching to Intravenous Dosing 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. 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 Adult Patients with Impaired Renal Function Recommended doses and adjustment for dose for adults are shown in Table 1. To use this dosing table, an estimate of the pati…

5 WARNINGS AND PRECAUTIONS • 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) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity: Discontinue if no alternative etiology (5.5) • Coordination Difficulties: Monitor for ataxia, abnormal gait, and incoordination. (5.6) • Withdrawal Seizures: Levetiracetam must be gradually withdrawn (5.7) 5.1 Psychiatric Reactions 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. 5.2 Somnolence and Fatigue 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 15912074A.indd 5 14.07.2025 09:38:44 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 …

4 CONTRAINDICATIONS 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)]. • Known hypersensitivity to levetiracetam; angioedema and anaphylaxis have occurred (4)

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including levetiracetam, during pregnancy. Encourage women who are taking levetiracetam injection during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary Prolonged experience with levetiracetam in pregnant women has not identified a drug-associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy registries and reflects experience over two decades [see Human Data]. In animal studies, levetiracetam produced developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) at doses similar to human therapeutic doses [see Animal Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Levetiracetam blood levels may decrease during pregnancy [see Warnings and Precautions (5.9)]. Physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester. Dose adjustments may be necessary to maintain clinical response. Data Human Data While available studies cannot definitively establish the absence of risk, data from the published literature and pregnancy registries have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage. Animal Data When levetiracetam (0, 400, 1200, or 3600 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and increased incidence of fetal skeletal variations were observed at the highest dose tested. There was no evidence of maternal toxicity. The no-effect dose for adverse effects on embryofetal development in rats (1200 mg/kg/day) is approximately 4 times the maximum recommended human dose (MRHD) of 3000 mg on a body surface area (mg/m2) basis. Oral administration of levetiracetam (0, 200, 600, or 1800 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and incidence of fetal skeletal variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which was associated with maternal toxicity. The no-effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately equivalent to the MRHD on a mg/m2 basis. Oral administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations, reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased pup mortality and neurobehavioral alterations in offspring at the highest dose tested. There was no evidence of maternal toxicity. The no-effect dose for adverse effects on pre- and postnatal development in rats (70 mg/kg/day) is less than the MRHD on a mg/m2 basis Oral administration of levetiracetam to rats during the latter part 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).

6 ADVERSE REACTIONS 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)] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.5)] • Coordination Difficulties [see Warnings and Precautions (5.6)] • Withdrawal Seizures [see Warnings and Precautions (5.7)] • Hematologic Abnormalities [see Warnings and Precautions (5.8)] • Seizure Control During Pregnancy [see Warnings and Precautions (5.9)] • Most common adverse reactions (incidence in levetiracetam-treated patients is ≥ 5% more than in placebo-treated patients) include: somnolence, asthenia, infection, and dizziness (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-332-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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. 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 2 lists 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. Table 2: Adverse Reactions* In Placebo-Controlled, Adjunctive Studies In Adults Experiencing Partial-Onset Seizures * Adverse reactions occurred in at least 1% of levetiracetam-treated patients and occurred more frequently than placebo-treated patients 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 3 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 3: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in Placebo- Controlled Studies in Adults Experiencing Partial-Onset Seizures Adverse Reaction Levetiracetam (N=769) % Placebo (N=439) % Somnolence 4 2 Dizziness 1 0 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 controlled c…